The Development of One New Normal Phase Liquid Chromatography Method and Thermodynamic Investigation of Olodaterol Hydrochloride Enantiomer.

In order to improve and replace the enantiomer method outlined in the olodaterol hydrochloride draft monograph (From the European Pharmacopoeia forum), one new, simple, and fast enantioselective normal phase high-performance liquid chromatography chiral method was developed on polysaccharide-based Chiral MX (2) (4.6 × 250 mm, 5 µm) column. n-Hexane, ethanol, and diethylamine in the ratio of 40:60:0.1 (V/V/V) were selected as mobile phase at a flow rate of 0.8 mL/min, and the detection was performed on a photodiode array detector at 225 nm with 5 µL injection volume. The column temperature was set at 40°C for better peak shape and sensitivity. The analysis time can be shortened to 15 min, whereas the resolution between enantiomer and olodaterol was found to be even more than 10.0, which was far better than that obtained with the reported method in this draft monograph. The developed chiral method was validated in accordance with ICH Q2 (R1), including specificity, LOD&LOQ, precision, linearity, accuracy, and robustness. Thereby, the proposed method was demonstrated to be suitable for the determination of enantiomer in olodaterol hydrochloride bulk drug and drug product. Besides, the thermodynamic parameters were evaluated on the basis of Van't Hoff plots that was used to explain correlative chiral recognition mechanisms with the chiral stationary phase.

Late-onset riboflavin-responsive multiple acyl-CoA dehydrogenase deficiency (MADD): case reports and epidemiology of ETFDH gene mutations.

BACKGROUND: Multiple acyl-CoA dehydrogenase deficiency (MADD) is a riboflavin-responsive lipid-storage myopathy caused by mutations in the EFTA, EFTB or ETFDH genes. We report a Chinese family of Southern Min origin with two affected siblings with late-onset riboflavin-responsive MADD due to a homozygous c.250G > A EFTDH mutation and review the genetic epidemiology of the c.250G > A mutation. CASE PRESENTATION: Both siblings presented with exercise-induced myalgia, progressive proximal muscle weakness and high levels of serum muscle enzymes and were initially diagnosed as polymyositis after a muscle biopsy. A repeat biopsy in one sibling subsequently showed features of lipid storage myopathy and genetic analysis identified a homozygous mutation (c.250G > A) in the ETFDH gene in both siblings and carriage of the same mutation by both parents. Glucocorticoid therapy led to improvement in muscle enzyme levels, but little change in muscle symptoms, and only after treatment with riboflavin was there marked improvement in exercise tolerance and muscle strength. The frequency and geographic distribution of the c.250G > A mutation were determined from a literature search for all previously reported cases of MADD with documented mutations. Our study found the c.250G > A mutation is the most common EFTDH mutation in riboflavin-responsive MADD (RR-MADD) and is most prevalent in China and South-East Asia where its epidemiology correlates with the distribution and migration patterns of the southern Min population in Southern China and neighbouring countries. CONCLUSIONS: Mutations in ETFDH should be screened for in individuals with lipid-storage myopathy to identify patients who are responsive to riboflavin. The c.250G > A mutation should be suspected particularly in individuals of southern Min Chinese background.

ViboPneumo: A Vibratory-Pneumatic Finger-Worn Haptic Device for Altering Perceived Texture Roughness in Mixed Reality.

Extensive research has been done in haptic feedback for texture simulation in virtual reality (VR). However, it is challenging to modify the perceived tactile texture of existing physical objects which usually serve as anchors for virtual objects in mixed reality (MR). In this paper, we present ViboPneumo, a finger-worn haptic device that uses vibratory-pneumatic feedback to modulate (i.e., increase and decrease) the perceived roughness of the material surface contacted by the user's fingerpad while supporting the perceived sensation of other haptic properties (e.g., temperature or stickiness) in MR. Our device includes a silicone-based pneumatic actuator that can lift the user's fingerpad on the physical surface to reduce the contact area for roughness decreasing, and an on-finger vibrator for roughness increasing. The results of our perceptual study showed that the participants could perceive changes in roughness, both increasing and decreasing, compared to the original material surface. We also observed the overlapping roughness ratings among certain haptic stimuli (i.e., vibrotactile and pneumatic) and the originally perceived roughness of some materials without any haptic feedback. This suggests the potential to alter the perceived texture of one type of material to another in terms of roughness (e.g., modifying the perceived texture of ceramics as glass). Lastly, a user study of MR experience showed that ViboPneumo could significantly improve the MR user experience, particularly for visual-haptic matching, compared to the condition of a bare finger. We also demonstrated a few application scenarios for ViboPneumo.

Degradation Mechanism Study for Secondary Degradants in Rosuvastatin Calcium and Determination of Degradant Acetaldehyde Using Static Headspace Gas Chromatography Coupled with Matrix Precipitation.

During the development of headspace gas chromatography (HSGC) method for assessing residual solvents in rosuvastatin calcium (RSV) drug substance, acetaldehyde (AA) was detected in obtained chromatograms, with a calculated concentration of up to 226 ppm. After a series of experiments, it was established that acetaldehyde originates from matrix interference due to direct degradation of Imp-C, which is accompanied by the formation of impurity at relative retention time (RRT) 2.18, without the involvement of impurity at RRT 2.31. The thermal instability of Imp-C also results in the formation of impurity at RRT 2.31 through dehydration and decarboxylation. In addition, cyclization reaction of degradant at RRT 2.18 further resulted in the generation of impurity at RRT 2.22. The structure of these three degradants, were confirmed by liquid chromatography-mass spectrometry (LC-MS), 1D and 2D nuclear magnetic resonance (NMR) measurement. In order to minimize the said matrix interference, a simple precipitation procedure was proposed as a pretreatment to mitigate the impact of Imp-C. Subsequently, an HSGC method was developed for the simultaneous determination of the degradant AA and the other five residual solvents used in RSV synthetic process. The final method was validated concerning precision, limit of detection (LOD) and limit of quantitation (LOQ), linearity, and accuracy.

PropelWalker: A Leg-Based Wearable System With Propeller-Based Force Feedback for Walking in Fluids in VR.

There has been an increasing focus on haptic interfaces for virtual reality (VR), to support a high-quality touch experience. However, it is still challenging to haptically simulate the real-world walking experience in different fluid mediums. To tackle this problem, we present PropelWalker, a pair of calf-worn haptic devices for simulating the buoyancy and the resistant force when the human's lower limbs are interacting with different fluids and materials in VR. By using four ducted fans, two installed on each calf, the system can control the strength and the direction of the airflow in real time to provide different levels of force. Our technical evaluation shows that PropelWalker can generate vertical forces up to 27N in two directions (i.e., upward and downward) within 0.85 seconds. Furthermore, the system can stably maintain the generated force with minor turbulence. We further conducted three user-perception studies to understand the capability of PropelWalker to generate distinguishable force stimuli. First, we conducted the just-noticeable-difference (JND) experiments to investigate the threshold of the human perception of on-leg air-flow force feedback. Our second perception study showed that users could distinguish four PropelWalker-generated force levels for simulating different walking mediums (i.e., dry ground, water, mud, and sand), with an average accuracy of 94.2%. Lastly, our VR user study showed that PropelWalker could significantly improve the users' sense of presence in VR.

Rational strategy of magnetic relaxation switches for glycoprotein sensing.

A rational strategy of magnetic relaxation switches was proposed here to detect a(1)-acid glycoprotein (AGP), an acute phase a-globulin plasma glycoprotein. The assay was based on the relaxation time change between the aggregation of magnetic nanoparticles with concanavalin A and the redispersion with AGP, which can avoid the prozone effect and improve the detection accuracy. The assay was an easy and efficient method with two mixing steps and one measurement step, showing a detection limit of 0.66 nM in 0~0.3 µg mL(-1) AGP, which was far lower than its normal level in human plasma.

A miniature chip for protein detection based on magnetic relaxation switches.

A miniature multi-sample chip for protein detection with a bench-top magnetic resonance imager was created on the basis of magnetic relaxation switches. The chip was assessed with two protein systems. Both qualitative and quantitative results for the target proteins were obtained by image analysis and relaxation time measurement, respectively. The detection of prostate specific antigen, the serum marker of human prostate cancer, showed a linear concentration range of 17.3-43.2 ng mL(-1) and a detection limit of 13.7 ng mL(-1). As proof of concept, the analysis of 18 samples with a volume of 6.37 µL each was completed in 26 min by this chip. This technique may become an easy and efficient approach for rapid and high-throughput protein assay and protein-protein interaction screening.

Magnetic relaxation switch and colorimetric detection of thrombin using aptamer-functionalized gold-coated iron oxide nanoparticles.

We describe a sensitive biosensing system combining magnetic relaxation switch diagnosis and colorimetric detection of human α-thrombin, based on the aptamer-protein interaction induced aggregation of Fe(3)O(4)@Au nanoparticles. To demonstrate the concept, gold-coated iron oxide nanoparticle was synthesized by iterative reduction of HAuCl(4) onto the dextran-coated Fe(3)O(4) nanoparticles. The resulting core-shell structure had a flowerlike shape with pretty narrow size distribution (referred to as "nanorose"). The two aptamers corresponding to human α-thrombin were conjugated separately to two distinct nanorose populations. Once a solution containing human α-thrombin was introduced, the nanoroses switched from a well dispersed state to an aggregated one, leading to a change in the spin-spin relaxation time (T(2)) as well as the UV-Vis absorption spectra of the solution. Thus the qualitative and quantitative detection method for human α-thrombin was established. The dual-mode detection is clearly advantageous in obtaining a more reliable result; the detection range is widened as well. By using the dual-mode detection method, a detectable T(2) change is observed with 1.0 nM human α-thrombin, and the detection range is from 1.6 nM to 30.4 nM.

A smart surface in a microfluidic chip for controlled protein separation.

The smart surface created in a microfluidic chip has shown the capability of adsorbing and releasing proteins under electrical control. The inner surface of the chip channel was first coated by a thin layer of Au through sputtering and was subsequently modified with loosely packed self-assembled monolayers (SAMs) of thiols with terminal carboxylic or amino groups. Upon application of an external electric potential to the gold substrate, reversible conformational transformation between "bent" and "straight" states for the anchored mercapto chains could be modulated, through the electrostatic effect between the ionized terminal groups and the charged gold substrate. Thus, a hydrophobic or hydrophilic channel surface was established and could be reversibly switched electrochemically. Accordingly, the microchips prepared in this way can reversibly and selectively adsorb and release differently charged proteins under electrical control. Two model proteins, avidin and streptavidin, were demonstrated to be readily adsorbed by the smart chips under negative and positive potential, respectively. Also, more than 90 % of the adsorbed proteins could be released upon an electrical command. Furthermore, these chips were applied to the controlled separation of avidin and streptavidin mixtures with 1:1 and 1:1000 molar ratios. Under specific applied potentials, the chips adsorbed a certain protein from the mixture whereas the other protein was allowed to flow out, after which the adsorbed protein could be released by switching the applied potential. Thus, two eluted protein fractions were obtained and the separation of the two proteins was achieved. For the former mixture, each eluted fraction contained up to approximately 80-90 % avidin or streptavidin. For the latter mixture, the resulting separation efficiency indicated that the molar ratio of avidin and streptavidin could be increased from 1:1000 to about 32:1 after five run separations.