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Studies on the neurobiological causes of anxiety disorders suggest that the GABA system in-creases synaptic concentration and enhances the affinity of GABAA (type A) receptors for ben-zo-diazepine ligands. Flumazenil antagonizes the benzodiazepine binding site of the GABA (γ-aminobutyric acid) type /benzodiazepine receptor (BZR) complex in the central nervous sys-tem (CNS). The integration of the metabolites of flumazenil by LC-tandem mass spectrometry will complete understanding of the in vivo metabolism of flumazenil and accelerate radio-pharmaceutical inspection and registration. The main goal of our study was to investigate using reversed-phase HPLC (PR-HPLC) coupled with electrospray ionization triple quadrupole tan-dem mass spectrometry (ESI-QqQ MS) for the identification of flumazenil and its metabolites in a hepatic matrix. And a carrier-free nucleophilic fluorination with automatic synthesizer for [18F]flumazenil which applied to in vivo nano-positron emission tomography (Nano-PET)/computed tomography (CT) imaging and ex vivo bio-distribution used to analyze in normal rats. The study showed that 50% of the flumazenil was bio-transformed at 60 min by the rat liver homogenate, while one metabolite (M1) was a methyl transesterification product of flumazenil. In a rat liver microsomes system, two metabolites were identified (M2 and M3) as its carboxylic acid and hydroxylated ethylester forms, respectively. [18F]flumazenil in vivo nanoPET/CT imag-ing and ex vivo bio-distribution assay also showed significant effects on GABAA receptor availa-bility in the amygdala, prefrontal cortex, cortex, and hippocampus in the rat brain, worriless about the formation of metabolites. We showed completion of the bio-transformed course of flumazenil by the hepatic system; and [18F]flumazenil can be a good ligand and serve as a PET agent for determination of GABAA/BZR complex for multiplex neurological syndromes in the clinical stage.

We present an approach to overcoming challenges in dynamical dexterity for robots through programmably compliant origami mechanisms. Our work leverages a one-parameter family of flat sheet crease patterns that folds into origami bellows, whose axial compliance can be tuned to select desired stiffness. Concentrically arranged cylinder pairs reliably manifest additive stiffness, extending the programmable range by nearly an order of magnitude and achieving bulk axial stiffness spanning 200–1500 Nm $^{-1}$ using 8 mil thick polyester-coated paper. Accordingly, we design origami energy-storing springs with a stiffness of 1035 N m $^{-1}$ each and incorporate them into a three degree-of-freedom (DOF) tendon-driven spatial pointing mechanism that exhibits trajectory tracking accuracy less than 15% rms error within a ( $\sim$ 2 cm) $^3$ volume. The origami springs can sustain high power throughput, enabling the robot to achieve asymptotically stable juggling for both highly elastic (1 kg resilient shotput ball) and highly damped (“medicine ball”) collisions in the vertical direction with apex heights approaching 10 cm. The results demonstrate that “soft” robotic mechanisms are able to perform a controlled, dynamically actuated task.

A high performance liquid chromatography tandem mass spectrometry (HPLC-MS/MS) analytical method was developed to determine the identity of impurities resulting from the synthesis of N,N-dimethyl-2-(2-amino-4-fluorophenylthio)benzyl-amine (F-ADAM), as well as its metabolic products by rat liver microsomes. 18F-ADAM is an important positive electron emission ligand commonly employed as a radio-imaging agent for serotonin transporter (SERT) in the brain. F-ADAM and its derivatives were separated using HPLC on a C4-phenyl column with an ammonium formate aqueous buffer/acetonitrile programmed mobile phase. Synthetic contaminants and metabolic products were identified using fragmentation spectra obtained by tandem mass spectrometry. We show that F-ADAM is unstable in methanol, and propose the use of acetonitrile to generate optimal chromatogram. A Cl-substituted species was found to be the major impurity resulting from the F-ADAM synthetic process. The metabolic products of F-ADAM by rat liver microsomes were characterized by oxidization of the sulfur moiety to sulfoxide, demethylation of the dimethylamine moiety, and oxidative defluorination/deamination. These results elucidate the by-products of F-ADAM synthetic and metabolic processes, and provide direction for the application of this imaging agent to biosystems properly.

m-Iodobenzylguanidinium hemisulfate (MIBGHS) is a precursor in the preparation of radioiodine-labeled m-iodobenzylguanidine (MIBG), which is used as a radio-imaging and therapy agent for neuroendocrine tumors and myocardial sympathetic nerve function. To ensure the quality and efficacy of the medicine and prevent side effects, the precursor purity, source of impurity, and derivatives have to be determined. In this study, the purity of synthesized MIBGHS and the amount of contaminants therein were determined by high-performance liquid chromatography and ultraviolet detection, gradient eluted by ammonium formate aqueous solution and acetonitrile mobile phase on both C8 and phenyl type column. The impurities were identified on the basis of molecular and fragmented ion mass spectra using of electrospray ionization triple quadrupole tandem mass spectrometry. The results revealed the presence of process-related impurities including m-bromobenzylguanidine (MBrBG) and overreacted byproducts. Stress test results indicated that MIBGHS is stable under acidic and dry thermal conditions for at least 72 h but MIBG aqueous solution was deteriorated slowly when exposed to UV light, thermal, oxidative and alkaline environments. Thus, m-iodobenzylamine, the starting material intended for the synthesis of MIBGHS should be analyzed to ensure that it is free from m-bromobenzylamine impurity. Stored under normal condition (-18°C), MIBGHS is stable for at least 12 months. The chemically labile guanidine and amine groups in MIBGHS are the major causes of its instability, while iodide loss from the phenyl group is a minor cause.

m-Iodobenzylguanidine hemisulfate (MIBGHS) is a precursor in the preparation of radioiodine-labeled m-iodobenzylguanidine (MIBG), which is used as a radio-imaging and therapy agent for neuroendocrine tumors and myocardial sympathetic nerve function. To ensure the quality and efficacy of the medicine and prevent side effects, the precursor purity, source of impurity, and derivatives have to be determined. In this study, the purity of synthesized MIBGHS and the amount of contaminants therein were determined by high-performance liquid chromatography and ultraviolet detection, gradient eluted by ammonium formate aqueous solution and acetonitrile mobile phase on both C8 and phenyl type column. The impurities were identified on the basis of molecular and fragmented ion mass spectra using of electrospray ionization triple quadrupole tandem mass spectrometry. The results revealed the presence of process- related impurities including m-bromobenzylguanidine (MBrBG) and overreacted byproducts. Stress test results indicated that MIBGHS is stable under acidic and dry thermal conditions for at least 72 h but MIBG aqueous solution was decomposes slowly when exposed to UV light, thermal, oxidative and alkaline environments. Thus, m-iodobenzylamine, the starting material intended for the synthesis of MIBGHS should be analyzed to ensure that it is free from m-bromobenzylamine impurity. Stored under normal condition (-18°C), MIBGHS is stable for at least 12 months. The chemically labile guanidine and amine groups in MIBGHS are the major causes of its instability, while iodide loss from the phenyl group is a minor cause. All contaminants, derivatives, and degenerates derived from the reaction activity of the guanidine or amine groups, and the weak phenyl-iodine bond of MIBG, they are non-toxic under normal medicinal dose, but may reduce the effective dose of radioiodine-labeled MIBG.

A reversed-phase high performance liquid chromatography (RP-HPLC) method for the purity assay of Sn-ADAM (2-((2-((Dimethylamino)methyl)phenyl)thio)-5-(tri-n-butyltin)-phenylamine) was developed and validated. Sn-ADAM is a precursor and free ligand of I-123-ADAM (I-123-2-([2-({dimethylamino}methyl)phenyl]thio)-5-iodophenylamine) that is a SPECT imaging agent for serotonin transporters (SERTs). The chromatographic separation for Sn-ADAM was achieved on a RP-18 column with an eluent consisting of methanol-acetonitrile-ammonium acetate (pH 7.0, 10 mM; 58.8 : 39.2 : 2, v/v/v). The absorbance at 220 nm against the concentration of Sn-ADAM was linear over the range of 9.9-317.8 ppm, with a correlation coefficient (r) of 0.99997. Method validation parameters, including specificity, linearity, precision, accuracy, LOD/LOQ, stability, robustness and suitability were evaluated, indicating the potential of this method in pharmaceutical quality control. Moreover, present results of precursor to product ion transitions of Sn-ADAM and I-127-ADAM by LC/ESI/MS/MS provided evidence for identification of fragmentation ions and proposition of the pathways of Sn-ADAM, I-127-ADAM and I-123-ADAM.

We report on experiments with a laptop-sized (0.23m, 2.53kg), paper origami robot that exhibits highly dynamic and stable two degree-of-freedom (circular boom) hopping at speeds in excess of 1.5 bl/s (body-lengths per second) at a specific resistance O(1) while achieving aerial phase apex states 25% above the stance height over thousands of cycles. Three conventional brushless DC motors load energy into the folded paper springs through pulley-borne cables whose sudden loss of tension upon touchdown triggers the release of spring potential that accelerates the body back through liftoff to flight with a 20W powerstroke, whereupon the toe angle is adjusted to regulate fore-aft speed. We also demonstrate in the vertical hopping mode the transparency of this actuation scheme by using proprioceptive contact detection with only motor encoder sensing. The combination of actuation and sensing shows potential to lower system complexity for tendon-driven robots.

In the field of haptics, conditions for mechanical “transparency” [1] entail such qualities as “solid virtual objects must feel stiff” and “free space must feel free” [2], suggesting that a suitable actuator is able both to do work and readily have work done on it.

High performance liquid chromatography coupled with tandem mass spectrometry was developed and validated as a method for the analysis of fluorinated histone deacetylase inhibitors (F-HDACi), and then employed to study their metabolism in biosystems. Four HDACi analogs labeled with the positron emission nuclide 18F constitute a group of potential positron emission tomography imaging agents, which were developed by the Institute of Nuclear Energy Research (INER) and coded as INER-1577 #1, #2, #3, and #4 during animal studies for the diagnosis of dementia. The performance of the method was found to be suitable for the determination of analog #3, and it was employed to determine the structures and fragmentation mechanisms of all four analogs and to study the biotransformations of analogs #3 and #4. The results indicated that the method used for the determination of analog #3 was suitable for determining the abundance of the analogs in chemical and biochemical tests with high precision, accuracy, reproducibility, and recovery. Weaknesses in the chemical bonding of the analogs were found to involve the fluoro, dimethylamino, and benzamide groups in a fragmentation mechanism deduced via tandem mass spectrometry. The metabolites of analogs #3 and #4 in rat liver microsomes and rat plasma were also identified to clarify their characteristic behaviors in biosystems. The major product of analogs #3 in liver microsomes was produced by hydroxylation of the benzylic carbon atom, but in rat plasma the metabolites of analog #3 were produced by hydrolysis of the benzamide group to give a diaminobiphenyl compound with the simultaneous replacement of a fluorine atom by a hydroxyl group. The metabolites of analog #4 in liver microsomes were produced by hydroxylation of the benzylic carbon atom and hydrolysis of the benzamide bond. The results of the studies characterized the chemical and biochemical behaviors of the series F-HADCi analogs.

Amitriptyline is an old drug but is still prevalently used as the first-line treatment for a variety of common diseases. Surprisingly, knowledge of sexual risks with amitriptyline comes from only one clinical trial and several case reports from three decades ago. In the current study, a systematic review of the literature following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) related to amitriptyline and sexual dysfunction (SD) was performed. The frequency, gender-difference, types, disease-specificity and time course of SD, and the relationship between SD and nonsexual adversity were studied. A total of 14 publications, including 8 qualified randomized clinical trials, were eligible. The frequency of SD in overall, male and female patients was 5.7, 11.9 and 1.7%, respectively. SD was six-fold higher in men than women. The frequency of SD was 6.9% in depressive patients compared with 0.8% in non-depressive patients ( p = .008), and gradually decreased at 8 weeks after treatment ( p = .02). Amitriptyline impacted arousal and libido more than orgasm and ejaculation in male patients but mainly libido in female patients. SD was significantly correlated with insomnia linearly whereas somnolence and nausea dually. Therefore, amitriptyline-associated SD mainly occurs in depressive and male patients, disturbs each phase of the sexual response cycle in men but mainly libido in women, gradually decreases under long-term treatment, and can be predicted by the co-existence of insomnia, somnolence or nausea during treatment. Clinicians should caution and tailor the gender and disease vulnerability of amitriptyline in their practice.

This report is on the design, control strategy, implementation, and performance evaluation of a novel leg–wheel transformable robot called TurboQuad, which can perform fast gait/mode coordination and transitions in wheeled mode, in legged trotting, and in legged walking while in motion. This functionality was achieved by including two novel setups in the robot that were not included in its predecessor, Quattroped. First, a new leg–wheel mechanism was used, in which the leg/wheel operation and its in situ transition can be driven by the same set of motors, so the actuation system and power can be utilized efficiently. Second, a bio-inspired control strategy was applied based on the central pattern generator and coupled oscillator networks, in which the gait/mode generation, coordination, and transitions can be integrally controlled. The robot was empirically built and its performances in the described three gaits/modes as well as the transitions among them were experimentally evaluated and will be discussed in this paper.

Objective Cheiro-pedal syndrome (CPS) is an incomplete sensory disorder confined to hand and foot and is generally considered a benign entity. However, knowledge comes from case report or case series only. The aim of this study is to clarify the etiology, localization and outcome of CPS. Patient and method A total of 21 CPS patients from our database and another 9 patients from literature were reviewed. CPS was classified into 4 types, namely unilateral and ipsilateral (Type I), bilateral (Type II), incomplete bilateral (Type III), and crossed (Type IV). Results They were 20 men and 10 women; including 20 Type I patients, 9 Type II patients, 1 Type III patients, and 0 Type IV patient. Vascular disorders, non-vascular cervical disorder and polyneuropathy were the responsible causes in 18 patients, 7 patients, and 2 patients, respectively. Etiology was unknown in another 3 patients. Lesions were located at brain parenchyma in 16 patients, and cervical cord above C5 level in 9 patients. Disable motoroparesis occurred between 4 days to 2 months in two-third of deteriorated patients. In three patients, their lesions were detected only on recurrence or exacerbation of CPS 4 months to 2 years later. Recovery, residual deficit and deterioration ensued in 44%, 28% and 28% patients, respectively. A 33.3% of brain involvement patients and 100.0% of spinal involvement patients terminated to residual deficit or deterioration. The sensitivity and specificity of prediction for deterioration was 77.8% and 100%, respectively, by type II or III CPS. Conclusion CPS is actually not a benign neurological disorder but a sensory alarm sign. A thorough examination of brain parenchyma and cervical spinal cord is urgent for identifying any treatable or preventable pathological lesions to reduce harmful consequence, especially in case of type II or III CPS.

Introduction: Headache associated with sexual activity (HSA) is the painful event of head and neck precipitated only by sexual activity. The negative impact of sexuality is expected to be more severe in HSA patients and their partners than other headache disorder. In addition, social and cultural taboo may conceal sexual problem or hinder seeking counseling for sexual perplexity. A sufficient scientific evidence is therefore needed to clarify the misunderstanding and schedule appropriate education in clinical practice. Methods: A systematic review of literature was completed to elucidate the sexual behavior, function and satisfaction in HSA patients and their partners. Results: A total of 97 publications are eligible after careful screening. However, most of the studies focus on the etiopathogenesis or treatment. Sexual change was mentioned in 23 publications. Orgasmic headache is the most frequent type of HSA. The HSA occurs more frequent in dyadic than extradyadic sexual activity. Intercourse is the leading sexual act for HSA occurrence, following by masturbation. A few patients suffer HSA under specific sexual position, like kneeling, and trigger, such as cannabis. Pain can be rapidly ceased in half of patients when sexual activity was halted. Sexual function and sexual satisfaction may decrease in HSA patient and partner but improve after pain reversal. Conclusions: A shortage of sexuality data of HSA is documented in literature but that still clarifies the extradyadic and masturbatory effect on HSA occurrence. Nevertheless, HSA disturbs sexual function and satisfaction in patients and their partners. The pathogenesis of pain includes two components, the hypersympathetic status and exertional action. Therefore, physician can schedule their education and counseling for HSA according to these findings. Further investigation for sexual function and satisfaction is warranted.

Introduction: Sexual response cycle is modulated by a variety of biological factors, especially antidepressants and antipsychotics. Although the circuit of romantic love has recently been delineated, the biological impact on romantic love is barely mentioned in human, however. Methods: In thus study, a comprehensive literature review was completed to elucidate the role of central monoamines, including dopamine, serotonin, norepinephrine, epinephrine, melatonin and histamine, for the romantic love and relationship in human. Results: The central circuit of romantic love includes the mesolimbic and mesocortical tract and their extensions widely distributed in cortical, subcortical and brainstem structures. The activation of brain foci progressively decreases along with the romantic relationship in many areas, including the bilateral caudate and ventral tegmentum area without change of passionate love. Hyperactivity of dopamine and serotonin is suggested at the synaptic level for romantic love in lovers, probably through an inhibition of transporters or increase of terminal release. Romantic love can be modulated by antidepressants or recreational drugs. Polymorphism of dopamine and serotonin receptor relates to the romantic relationship. The effect of other monoamines is barely mentioned. Conclusions: Romantic love is vulnerable for secondary effect, such as drugs which modulate the dopamine and serotonin, in human. Romantic relationship is also impacted by the polymorphism of monoamine receptors. Therefore, the biological effect is not limited to sexual response cycle but also the romantic love and relationship. Further investigation is warranted for understanding the secondary effect in romantic love for romantic dissolution or divorce.

Background: Low lipid level is associated with better cardiovascular outcome. However, lipid paradox indicating low lipid level having worse outcomes could be seen under acute injury in some diseases. The present study was designed to clarify the prognostic significance of acute-phase lipid levels within 1 day after admission for stroke on mortality in first-ever statin-naïve acute ischemic stroke (IS) and hemorrhagic stroke (HS).Methods: This observational study was conducted using the data collected from Stroke Registry In Chang-Gung Healthcare System (SRICHS) between 2009 and 2012. Patients with recurrent stroke, onset of symptoms >1 day, and history of the use of lipid-lowering agents prior to index stroke were excluded. Stroke was classified into IS and hypertension-related HS. The primary outcomes were 30-day and 1-year mortality identified by linkage to national death registry for date and cause of death. Receiver operating characteristic (ROC) curve analysis and multivariate Cox proportional hazard models were used to examine the association of lipid profiles on admission with mortality.Results: Among the 18,268 admitted stroke patients, 3,746 IS and 465 HS patients were eligible for analysis. In IS, total cholesterol (TC)

Objectives Spontaneous orgasm is characterized by a spontaneous onset of orgasm without any preceding sexual or nonsexual trigger. It sheds insight on the mechanisms underlying orgasms and the sexual response cycle in humans. Methods We report a male patient of repetitive spontaneous orgasm under trazodone treatment and systematically review the literature on drug-associated spontaneous orgasm (DASO). Results A total of 25 patients (18 women and 7 men), including our reported case, experienced 27 DASO events. Over half of them were under 50 years of age during the DASO event. Depression was the leading morbidity for these patients, and a limited list of antidepressants and antipsychotics were involved in 92.5% of all DASO events. Although offending drugs possess variable pharmacological properties, their common effect is an augmentation of serotonin-1A (5HT1A) neurotransmission. Offending drugs seemingly increase personal susceptibility to DASO. Over half of the patients, especially men, did not concurrently experience sexual arousal or desire during the DASO event. In the remaining patients, the orgasm was accompanied by or ensued with arousal or desire. A reduction of dose or discontinuation of the offending drug usually abolished DASO. Conclusions It appears that 5HT1A has a key role in generating orgasm. Orgasms may be activated through arousal-independent or arousal-dependent pathways, and both orgasms and sexual arousal are bidirectionally activated. This double-bidirectional model of sexual response cycle may promote the success of sexual procreation and recreation, and further research on this pathway could offer an innovative method to manage anorgasmia in the future.

SummaryEndothelial dysfunction leads to worse cognitive performance in Alzheimer’s dementia (AD). While both cerebrovascular risk factors and endothelial dysfunction lead to activation of vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1) and E-selectin, it is not known whether these biomarkers extend the diagnostic repertoire in reflecting intracerebral structural damage or cognitive performance. A total of 110 AD patients and 50 age-matched controls were enrolled. Plasma levels of VCAM-1, ICAM-1 and E-selectin were measured and correlated with the cognitive performance, white matter macro-structural changes, and major tract-specific fractional anisotropy quantification. The AD patients were further stratified by clinical dementia rating score (mild dementia, n=60; moderate-to-severe dementia, n=50). Compared with the controls, plasma levels of VCAM-1 (p< 0.001), ICAM-1 (p=0.028) and E-selectin (p=0.016) were significantly higher in the patients, but only VCAM-1 levels significantly reflected the severity of dementia (p< 0.001). In addition, only VCAM-1 levels showed an association with macro- and micro- white matter changes especially in the superior longitudinal fasciculus (p< 0.001), posterior thalamic radiation (p=0.002), stria terminalis (p=0.002) and corpus callosum (p=0.009), and were independent of, age and cortical volume. These tracts show significant association with MMSE, short term memory and visuospatial function. Meanwhile, while VCAM-1 level correlated significantly with short-term memory (p=0.026) and drawing (p=0.025) scores in the AD patients after adjusting for age and education, the significance disappeared after adjusting for global FA. Endothelial activation, especially VCAM-1, was of clinical significance in AD that reflects macro- and micro-structural changes and poor short term memory and visuospatial function.

Objectives In contrast to previous concept that tinnitus is confined to an otologic disorder, current evidence supports it as a phantom sensory phenomenon of vestibulocochlear damage with cortical reorganization. It is a common problem worldwide, but the treatment response is always unsatisfactory. Patients and Methods In this study, we report 10 patients who described their staccato tinnitus as simulating the ticking sound of a pendulum or quartz clock (or termed clocking tinnitus). The tinnitus characteristics, laboratory tests, and treatment response were recorded. Results Clocking tinnitus was unilateral in three patients, bilateral in one patient, and at midline in another six patients. It usually subsided within 15 min. Neither patient experienced vertigo, hemifacial spasm, focal neurological deficit or otic disorder in association with tinnitus. Pre-existing migraine was present in seven patients. During tinnitus attack, a few migraine symptoms concurrently occurred in six patients. Pure-tone audiometry showed symmetric sloping pattern of hearing impairment in half patients whereas brainstem auditory evoked potentials revealed a prolonged wave I-III latency in 30% of patients. The p300 and electroencephalogram were normal in all of them. Neuroimaging study did not disclose structural change. All patients responded poorly to conventional treatments but favorably to flunarizine or topiramate. Conclusion Clocking tinnitus may be an audiology manifestation of migraine in some individuals. Antimigraine treatment can be considered in this specific group of staccato tinnitus. Audiogenic classification of tinnitus may provide diagnostic and treatment clues in tinnitus patients.

Background: Patients with minor acute ischemic stroke or transient ischemic attack are at high risk for subsequent stroke, and more potent antiplatelet therapy in the acute setting is needed. However, the potential benefit of more intense antiplatelet therapy must be assessed in relation to the risk for major bleeding. The SOCRATES trial (Acute Stroke or Transient Ischemic Attack Treated With Aspirin or Ticagrelor and Patient Outcomes) was the first trial with ticagrelor in patients with acute ischemic stroke or transient ischemic attack in which the efficacy and safety of ticagrelor were compared with those of aspirin. The main safety objective was assessment of PLATO (Platelet Inhibition and Patient Outcomes)–defined major bleeds on treatment, with special focus on intracranial hemorrhage (ICrH). Methods: An independent adjudication committee blinded to study treatment classified bleeds according to the PLATO, TIMI (Thrombolysis in Myocardial Infarction), and GUSTO (Global Use of Strategies to Open Occluded Coronary Arteries) definitions. The definitions of ICrH and major bleeding excluded cerebral microbleeds and asymptomatic hemorrhagic transformations of cerebral infarctions so that the definitions better discriminated important events in the acute stroke population. Results: A total of 13 130 of 13 199 randomized patients received at least 1 dose of study drug and were included in the safety analysis set. PLATO major bleeds occurred in 31 patients (0.5%) on ticagrelor and 38 patients (0.6%) on aspirin (hazard ratio, 0.83; 95% confidence interval, 0.52–1.34). The most common locations of major bleeds were intracranial and gastrointestinal. ICrH was reported in 12 patients (0.2%) on ticagrelor and 18 patients (0.3%) on aspirin. Thirteen of all 30 ICrHs (4 on ticagrelor and 9 on aspirin) were hemorrhagic strokes, and 4 (2 in each group) were symptomatic hemorrhagic transformations of brain infarctions. The ICrHs were spontaneous in 6 and 13, traumatic in 3 and 3, and procedural in 3 and 2 patients on ticagrelor and aspirin, respectively. In total, 9 fatal bleeds occurred on ticagrelor and 4 on aspirin. The composite of ICrH or fatal bleeding included 15 patients on ticagrelor and 18 on aspirin. Independently of bleeding classification, PLATO, TIMI, or GUSTO, the relative difference between treatments for major/severe bleeds was similar. Nonmajor bleeds were more common on ticagrelor. Conclusions: Antiplatelet therapy with ticagrelor in patients with acute ischemic stroke or transient ischemic attack showed a bleeding profile similar to that of aspirin for major bleeds. There were few ICrHs. Clinical Trial Registration: URL: http://www.clinicaltrials.gov . Unique identifier: NCT01994720.

The headache associated with intercourse or masturbatory activity is a well-recognized clinical entity but pornography headache is barely mentioned. We report a young man who suffered preorgasmic headache pertaining only to pornography of specific erotic contents but not to other sexual or nonsexual act. An antecedent activation of sexual arousal and vasoconstriction during pain were found. Finally, oral indomethacin favorably prevented the pain. Therefore, pornography headache is a distinguished headache disorder distinct from other sexual-related headache disorders. Sexual arousal-mediated cerebrovascular dysregulation consequence to visuoneural uncoupling in response to erotic stimulus is proposed. Pornography headache may be underestimated in population as pain-killer overuse may mask the actual incidence in real world.

The labeling process stability of a radiopharmaceutical, radio isotope rhenium-labeled N-[2-mercaptoethyl]- 3-aza-19-ethyloxycarbonyl-3-[2-mercaptoethyl] octadecanoate (188Re-MN-16ET) for treatment of hepatocellular carcinoma (HCC) from its precursor, triphenylmethyl (Ph3C-) group protected-MN-16ET with 188ReO4- was surveyed and identified the derivatives from both reactant and product. After incubation for various specified periods of up to 6 h under various labeling reaction conditions, including acetic acid or mixed with normal saline, room temperature or a reaction temperature of 100°C, and the radiolytic effect of Re-188, the levels of protected-MN-16ET and Re-MN- 16ET in solutions were analyzed by high performance liquid chromatography-tandem mass spectrometry (HPLCMS/ MS) to study the impacts of the labeling process on their structural stabilities and the derivatives that arise from decomposition when preparing 188Re-MN-16ET from stock solution. This information is the key to determine whether 188Re-MN-16ET is structurally accurate and suitable for its intended use. The results showed that the major factor that impacts the structural stability of the product, Re-MN-16ET, is 188ReO4-; however, a thermal (100°C) effect on the precursor, protected-MN-16ET, was also observed. After 1 h incubation with 188ReO4- (100°C), the abundances of Re-MN-16ET and protected-MN-16ET were reduced by approximately 15% and 25%, respectively. The major decomposition products were Re-MN-16COOH and intra-molecular disulfide derivative. Moreover, the auto-radiolysis effect of Re-188 (60 mCi) on 188Re-MN-16ET was not clearly observable until 140 h. On the other hand, a stability study of Re-MN-16ET in plasma showed that 8% remained after incubation for 1 h; the metabolite was Re-MN-16COOH, which is identical to the hepatic bio-transformed product.

The radio-isotope rhenium-labeled N-[2-(triphenylmethyl)thioethyl]-3-aza-19-ethyloxycarbonyl-3-[2-(triphenylmethyl)thioethyl] octadecanoate) ligand (188Re-MN-16ET) is a novel therapeutic agent under preclinical evaluation for hepatoma. A reversed-phase high performance liquid chromatography coupled with a tandem mass spectrometric analysis method and diode array detector (DAD) involving a T type splitter was developed to characterize this pharmaceutical in rat liver tissue solution and determine its biotransformation rate. The separation was accomplished on a C18 column (chromolith silica, 4.6 mm × 100 mm) using an acetonitrile–ammonium acetate buffer gradient as the mobile phase. The detection was achieved by DAD set at 250 nm and tandem mass spectrometry using electrospray ionization in the positive ion mode. Re-MN-16ET displayed a retention time of 23.2 min and a transition ion pair corresponding to m/z 677 → 631 for multiple reaction monitoring. Its biotransformation reaction in rat liver homogenate proceeded for 90 min in a 37°C water bath. The characterization was conducted using aliquots that were extracted and concentrated from the reaction mixture for various incubation times. Re-MN-16ET exhibited a biotransformation half-life ( t1/2) of 8–9 min in liver tissue solution and was almost completely exhausted after 90 min. Two of its metabolites, consisting of the Re-labeled carboxylic acid derivative, predominately, and its corresponding demetallized disulfide ligand were found in the liver homogenate, providing a metabolism pathway for the radiopharmaceutical.

A reversed-phase high-performance liquid chromatography (HPLC) and liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was applied to study the forced degradation behavior and stability of epidepride. 123 I radioisotope-labeled epidepride, [(-)- N -{[(2 S )-1-ethylpyrrolidin-2-yl]methyl}-5-iodo-2,3- dimethoxybenzamide] is a radiotracer with a high affinity for dopamine D 2 receptors in the brain and has been used as an imaging agent for single-photon emission computed tomography. HPLC studies were performed using 127 I-epidepride (the nonradioactive compound), instead of 123 I-epidepride, with an RP-18 column using a mobile phase consisting of methanol, acetonitrile, and ammonium acetate (pH 7.0, 10 mM). The eluent flow rate and the wavelength for HPLC detection were 0.5 mL/min and 210 nm, respectively. The ligand was exposed to acid (1 N HCl) and alkaline (1 N NaOH) media and was subjected to oxidative decomposition at room temperature using 3% H 2 O 2 and to thermal decomposition at 50°C. After various reaction times (30 minutes, 1 hour, 2 hours, 8 hours, and 24 hours), the substances were investigated by HPLC and LC-MS/MS. Although no decomposition products were observed after the acidic, alkaline, and thermal treatments, >80% of the initial amount of 127 I-epidepride was oxidized within 24 hours in the presence of H 2 O 2 . Only one major oxidation product with an m/z value of 435 was observed, in addition to the 127 I-epidepride species (m/z 419). The product was characterized by LC-MS/MS fragmentation, and the deteriorated type and fragmentation pathways were proposed for epidepride.

A non-peptide inhibitor that is metabolically stable, orally active and capable of crossing the blood–brain barrier has been a popular option for treating Alzheimer's disease (AD). To identify novel non-peptide inhibitors for AD drug development, a structure-based pharmacophore model (SBPM) was developed using the representative docked conformation of the recently discovered peptide inhibitor PGKLVYA in the potential binding site on the Aβ(17–42) protofibril. The best SBPM, consisting of two hydrophobic, one hydrogen bond donor, and one positive ionisable feature, was further validated using ligand pharmacophore mapping studies. The well-validated SBPM was then used as the 3D query in virtual screening to identify potential hits from the National Cancer Institute database. These hits were subsequently filtered by toxicity prediction and molecular docking, and their binding stabilities and affinities were validated by 20-ns molecular dynamics simulations and molecular mechanics Poisson–Boltzmann surface ar...

This paper reports on the design, integration, and performance evaluation of a novel four-leg/four-wheel transformable mobile robot, Quattroped. In contrast to most hybrid platforms that have separate mechanisms and actuators for wheels and legs, this robot is implemented with a unique transformation mechanism that directly switches the morphology of the driving mechanism between the wheels (i.e., a full circle) and 2 degrees of freedom leg (i.e., combining two half circles as a leg), so that the same system of actuation power can be efficiently utilized in both wheeled and legged modes. The design process, mechatronics, software infrastructure, behavioral development, and leg-wheel dynamic characteristics are described. The performance of the robot is evaluated in various scenarios, including driving and turning in wheeled mode, driving, step and bar crossing, irregular terrain passing, and stair climbing in legged mode. Taking advantage of the leg-wheel combination on a single platform, the comparison of the wheeled and legged locomotion is also discussed.

Inhibition of anthrax lethal factor (LF) has been reported to be a potent strategy for the treatment of anthrax; however, no effective LF inhibitors are currently available. In this study, a structure-based pharmacophore model was developed based on the co-crystallized structure of anthrax LF with the active inhibitor GM6001. The best pharmacophore model (denoted as SB_Hypo1), consisting of two hydrogen bond acceptors, one hydrogen bond donor and one hydrophobic, was further validated using Gunner-Henry score method. The well-validated SB_Hypo1 was then used as a 3D-query in virtual screening to identify potential hits from NCI database. These hits were subsequently filtered by ADMET and validated by molecular docking experiments, and their binding stabilities were validated by 10-ns MD simulations. Finally, three hits were identified as potential leads based on their favorable binding interactions.

Benign prostatic hyperplasia (BPH) is caused by augmented levels of androgen dihydrotestosterone (DHT) which is involved in the growth of the prostate in humans. 5α-Reductase type II (5αR2) is an intracellular enzyme that catalyses the formation of DHT from testosterone; hence, the inhibition of 5αR2 has emerged as one of the most promising strategies for the treatment of BPH. In this study, a computational approach that integrates ligand-based pharmacophore modelling, virtual screening, molecular docking and molecular dynamics (MD) simulations was adopted to discover novel 5αR2 inhibitors with less side effects. After validating by Fischer's randomisation and Guner–Henry test, the best quantitative pharmacophore model (Hypo1), consisting of two hydrogen-bond acceptors and three hydrophobic features, was subsequently used as a three-dimensional-query in virtual screening to identify potential hits from Maybridge and National Cancer Institute databases. These hits were further filtered by ADMET (absorption...

Introduction Sexual pharmacotoxicity renders patients with epilepsy at a risk for sexual dysfunction (SD). This study is aimed to analyze the relationship between sexual function and topiramate to avoid topiramate-associated SD. Methods A systematic review following the PRISMA guidelines was performed to elucidate any SD occurrence in patients receiving topiramate. Results A total of 17 publications were reviewed. Based on limited polytherapy observational studies, the frequency of self-reported topiramate-associated SD, libido disorder, and orgasmic disorder in patients with polytherapy was 9.0%, 9.0%, and 2.6%, respectively (grade C evidence). Female patients mainly had anorgasmia, whereas male patients principally had erectile dysfunction. The daily dose of topiramate in patients with SD was within the recommended dose. Sexual adversity usually occurred from 4 weeks after topiramate use but favorably subsided without eventful complications after topiramate substitution or dose reduction in all patients. Conclusions Topiramate can elicit different patterns of SD, especially anorgasmia in women and erectile dysfunction in men, even with a therapeutic dose. Detailed drug education and careful monitoring are necessary to maximize sexual health, especially in persons undergoing polytherapy and with other risks for SD. Moreover, a rapid response, such as substitution or reduction of the dose, is suggested when SD occurs during its use.

Transthyretin (TTR) is a homotetrameric plasma protein associated with human amyloid diseases. Although Tafamidis has been recently approved for the treatment of TTR familial amyloid polyneuropathy (FAP), there is still a need for more effective drugs in the treatment of TTR amyloidosis diseases. In this study, a computer-aided approach combining molecular docking, virtual screening and molecular dynamics (MD) simulations was employed to identify potent TTR amyloidosis inhibitors from National Cancer Institute (NCI), Maybridge and Asdi databases. A receptor-specific scoring function was also developed using comparative binding energy (COMBINE) method to accurately predict the inhibitory activities for the selected compounds during virtual screening. The developed receptor-specific scoring function demonstrated good predictive ability by yielding strong correlation coefficients between experimental activities and estimated activities for 32 training set and 9 test set compounds, respectively. Moreover, it was successfully applied to rank the candidate compounds from structure-based virtual screening. Finally, three compounds (NSC220163, MFCD00276817 and SPB06319) were identified as potential leads, which exhibited higher predicted inhibitory activities and higher binding affinities in comparison to the Tafamidis. Our results further suggest that halogen bonding interaction plays a crucial role in stabilizing the TTR-inhibitor complex. These results indicate that our computational approach could effectively discover more potent TTR amyloidosis inhibitors, which can be further validate by in vitro and in vivo biological tests.

We designed and implemented a novel omnidirectional spherical robot. Instead of using wheels or flywheels, a driven ball is installed inside the spherical shell and driven by two orthogonally-mounted rollers; thus, the omnidirectional mobility of the robot with no singularity can be achieved by simple forward kinematic mapping. The dynamic model of the robot is derived, and effect of the model's parameters is evaluated in simulation and discussed. The simulation results also serve as the design guideline for building the empirical system. Several design issues are addressed to ensure the robot's proper development. Finally, the spherical robot is built, and its performance is quantitatively and experimentally evaluated, thus proving its omnidirectional and trajectory-controllable mobility.

Although a previous or recent history of varicella-zoster virus (VZV) infection is known to increase the risk of stroke in both children and adults, the influence of zoster sine herpetic remains unclear. We report an immunocompetent man with common cold symptoms and conjunctivitis, followed by an acute onset of bulbar weakness and hemihypesthesia without preceding skin rash. Acute medullary infarction and left vertebral artery stenosis were detected. VZV infection was finally identified. Zoster sine herpetic interferes with accurate diagnosis of infectious stroke, and vertebral artery involvement is unusual in ischemic stroke in this situation. An unexplained course of ischemic stroke event should be suspected in patients with VZV cerebrovasculopathy, especially in those without conventional stroke risk factors and those exhibiting concomitant infectious complications.

Paramethoxymethamphetamine (PMMA) is an emerging and prevalent psychoactive drug with a structure analogous to amphetamine and related psychostimulants. However, the neurobehavioral effect is only studied in experimental animals and is barely mentioned in human. The authors report the antemortem neurobehavioral manifestations in 8 patients with PMMA use. There were 2 different antemortem presentations. The first group of patients showed delirium, hypertalkativity, and incoherence speech and then turned into convulsion and death. They did not exhibit the typical hyperdopaminergic movement disorder. The second group of patients gradually fell asleep and then suffered respiratory or cardiovascular collapse. The heart blood PMMA level was higher in the second group than in the first group of patients. Forensic autopsy showed variable findings, ranging from no remarkable change to significant pathological damage similar to serotonin syndrome in both groups of patients. PMMA seems to enhance serotoninergism than dopaminergism, and exerts a concentration-related dual effect on human.

Understanding the nature of the recognition between amyloid protofibrils and dye molecules at the molecular level is essential to improving instructive guides for designing novel molecular probes or new inhibitors. However, the atomic details of the binding between dyes and amyloid fibrils are still not fully understood. In this study, molecular docking, consensus scoring, molecular dynamics (MD), and molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) analyses were integrated to investigate the binding between Congo red (CR) and the GNNQQNY protofibril from yeast prion protein Sup35 and to further evaluate their binding stabilities and affinities. Our results reveal that there are four CR binding sites located on GNNQQNY protofibril surface. These four CR binding sites adopt dual binding modes by which CR binding with its long axis parallel and perpendicular to the long axis of the protofibril. In addition, CR was also found to bind to the edge of the protofibril via hydrophobic/aromatic and hydrogen-bonding interactions, which is inferred as the possible inhibition mechanism to prevent the elongation of the protofibril from the addition of incoming peptides. Virtual screening from National Cancer Institute (NCI) database obtained three hit compounds with higher binding affinity than CR to the edge of the protofibril due to the fact that the central parts of these compounds are able to form additional hydrogen bonds with the protofibril. The results of the study could be useful for the development of new molecular probes or inhibitors for clinical applications.

Cheiro-pedal syndrome (CPS) is an incomplete pure sensory disorder confined strictly to simultaneous hand/finger and ipsilateral foot/toe symptoms. However, its clinical significance and pathogenesis are unclear. We present nine patients with typical CPS, and review another seven previously reported patients. Ischemic stroke is the leading cause of CPS in these 16 patients. In 13 patients, the lesions responsible were distributed widely in the brain from the corona radiata to the medulla oblongata whereas in three patients the lesions were found in the cervical spinal cord or peripheral nerves. All patients had a favorable outcome. The close proximity of the cheiral and pedal sensory fibers in the pons, thalamus, internal capsule and the caudal thalamocortical projection increases the vulnerability for CPS. Therefore, the underlying cause of CPS should be investigated rapidly despite it causing only minor symptoms. The pathogenesis of CPS may consist of several interacting factors including preconditioned neuronal damage and proximity of the acral sensory fibers.

This study presents a supplementary cepstrum-based scheme to achieve blind audio watermarking via the mean-value manipulation. The proposed scheme can work with the conventional statistical mean manipulation to double the watermark capacity under the same framework. As these two cepstral schemes affect the spectrum in low frequencies in a superposition manner, the developed watermarking system employs the conventional scheme to initiate a start and the new one to actually embed watermark bits. During the embedding phase, the rapid variations between frames caused by the watermarking process are avoided by adding a transition space. In addition, the watermarking system maintains data synchronization through the insertion of a sinusoid-like signal which keeps synchronization with the frame rate. Experimental results confirm the robustness of the proposed scheme against various attacks, including time-scaling and time-shifting that many other watermarking techniques failed to survive through.

In this paper, we have demonstrated that the thymine linker length number (Tn, n = 0–60) and stem pair number (Pm, m = 0–16) in the terminal of thrombin binding aptamers (TBAs) have a strong impact on the flexibility and stability of TBA-modified gold nanoparticles (TBA–Au NPs) and thus the binding strength and inhibitory potency toward thrombin. The anticoagulation of TBA–Au NPs increased with an increase in the linker length from T0 to T30 due to an increase in the flexibility of G-quadruplexes of TBAs on the Au NP surfaces (TBA-Tn–Au NPs). The inhibition of TBA-PmT15–Au NPs increased with an increase in the Pm from P0 to P8 as a result of the increase in the rigidity and the stability of G-quadruplexes of the TBAs on the Au NP surfaces. The best results were observed for multivalent TBA–Au NPs conjugates—TBA15/TBA29-P8T15–Au NPs—which exhibited ultra-high binding affinity toward thrombin (Kd = 8.86 × 10−12 M) and thus extremely high anticoagulant (inhibitory) potency because of their particularly flexible and stable conformation and multivalency. Compared to the case without inhibitors, their measured thrombin clotting time (TCT) was 296 times longer, whereas for TBA15 alone it was only 3.9 times longer. From the dosage dependence of the TCT delay, we further demonstrated the anticoagulation ability of our TBA15/TBA29-P8T15–Au NPs was much better than the commercial drugs (argatroban and hirudin). Moreover, the Au NPs modified with TBA with photocleavable (PC) units allow a reversal in the activity of TBAPC–Au NPs via near-UV light-inducement of TBA release from Au NPs. We believe that our described techniques can be used widely to modify NPs with other anticoagulant DNA or RNA aptamers towards different proteins such as factor IX, activated protein C, and factor VIIa.

We report a 75-year-old male patient who suffered posterior circulation ischaemia after influenza A/H1N1 vaccination. Vaccination provokes a variable magnitude of inflammatory and immunological response that modifies the risk for ischaemic stroke. Whereas a causal relation between vaccination and ischaemic stroke is still unsettled, an inflammatory/immunological response after vaccination may trigger thrombosis superimposing a pre-existing prothrombotic state. Careful monitoring is strongly suggested for individuals who received H1N1 vaccine, especially those with high ischaemic stroke risk.