Acetaminophen improves tardive akathisia induced by dopamine D₂ receptor antagonists

Tardive akathisia is a movement disorder characterized by internal restlessness with an uncontrollable urge to move, leading to repetitive movements. It is a common side effect of long-term treatment with dopamine D₂ receptor antagonists. In the present study, we analyzed the FDA Adverse Event Reporting System and IBM MarketScan Research Database to find a drug that can be used concomitantly with dopamine D₂ receptor antagonists and still reduce the risk of akathisia. Acetaminophen was determined to be the most effective akathisia-suppressing drug. In an experimental validation of the hypothesis, chronic treatment of rats with haloperidol caused akathisia symptoms, including increased stereotyped behavior and locomotor activity, and decreased immobility time. Acute treatment with acetaminophen significantly attenuated haloperidol-induced akathisia. In the ventral striata of these rats, acetaminophen prevented haloperidol-induced decrease in the number of c-Fos⁺ preproenkephalin⁺ neurons. These results suggest that acetaminophen is effective in suppressing tardive akathisia by activating indirect-pathway medium spiny neurons

Asymmetrical membrane fluidity of bovine adrenal chromaffin cells and granules and effect of trichosporin-B-VIa

AbstractWe examined membrane fluidity of bovine adrenal chromaffin cells and chromaffin granules using cationic trimethylammonium derivative of diphenylhexatriene (TMA-DPH) as a fluorescence probe. After adding TMA-DPH to the suspension of chromaffin cells and that of granules, it first bound to the outer layer of the plasma membrane of the cells and that of the granule membrane, then gradually penetrated the inner layer of each membrane and distributed to both leaflets of the respective membranes. Accompanying increases in the ratio of incorporated probe on the cytoplasmic side of the chromaffin cell membrane, its fluorescence anisotropy gradually decreased. However, in chromaffin granules, the fluorescence anisotropy gradually increased with increases in the ratio of incorporated probe. These findings suggest that the inner layer of the plasma membrane and outer layer of the granular membrane are more fluid than the corresponding side of each membrane, which is suitable for the fusion between both membranes. We also examined the effect of trichosporin-B-VIa, a fungal ion channel forming α-aminoisobutyric acid-containing peptide, on the fluidity of chromaffin cells using TMA-DPH. The peptide decreased the fluorescence anisotropy and increased the fluorescence intensity in the concentration range that induced Ca2+ dependent catecholamine secretion, suggesting that a change in lipid dynamics of the lipid bilayer of the plasma membrane was induced by this peptide

Bilateral Renal Cell Carcinoma and its Treatment

A report is presented on two cases of bilateral renal cell carcinoma together with a review of the literature. Bilateral renal cell carcinoma is rare and there is much controversy concerning its treatment. Our current experience supports conservative therapy for bilateral renal cell carcinoma

Striatal TRPV1 activation by acetaminophen ameliorates dopamine D2 receptor antagonists-induced orofacial dyskinesia

ジスキネジア新治療法の発見 --副作用を減らす併用薬から新しい創薬標的へ--. 京都大学プレスリリース. 2021-04-16.Antipsychotics often cause tardive dyskinesia, an adverse symptom of involuntary hyperkinetic movements. Analysis of the U.S. Food and Drug Administration Adverse Event Reporting System and JMDC insurance claims revealed that acetaminophen prevents the dyskinesia induced by dopamine D₂ receptor antagonists. In vivo experiments further showed that a 21-day treatment with haloperidol increased the number of vacuous chewing movements (VCMs) in rats, an effect that was inhibited by oral acetaminophen treatment or intracerebroventricular injection of N-(4-hydroxyphenyl)-arachidonylamide (AM404), an acetaminophen metabolite that acts as an activator of the transient receptor potential vanilloid 1 (TRPV1). In mice, haloperidol-induced VCMs were also mitigated by treatment with AM404 applied to the dorsal striatum, but not in TRPV1-deficient mice. Acetaminophen prevented the haloperidol-induced decrease in the number of c-Fos⁺/preproenkephalin⁺ striatal neurons in wild-type mice but not in TRPV1-deficient mice. Finally, chemogenetic stimulation of indirect-pathway medium spiny neurons in the dorsal striatum decreased haloperidol-induced VCMs. These results suggest that acetaminophen activates the indirect pathway neurons by activating TRPV1 channels via AM404

Exploring deuterium beam operation and the behavior of the co-extracted electron current in a negative-ion-based neutral beam injector

The achievements of the deuterium beam operation of a negative-ion-based neutral beam injector (N-NBI) in the large helical device (LHD) are reported. In beam operation in LHD-NBIs, both hydrogen (H) and deuterium (D) neutral beams were generated by changing the operation gas using the same accelerator. The maximum accelerated deuterium negative-ion current () reaches 46.2 A from two beam sources with the averaged current density being 190 A m−2 for 2 s, and the extracted electron to accelerated ion current ratio () increases to 0.39 using 5.6 V high bias voltage in the first deuterium operation in 2017. An increase of electron density in the vicinity of the plasma grid (PG) surface, which is considered the main reason for the increase of co-extracted electrons in a beam, is confirmed by the half-size research negative-ion source in the neutral beam test stand at the National Institute for Fusion Science (NIFS). The deuterium negative-ion density is also larger than the hydrogen negative-ion density in the vicinity of the PG surface using the same discharge conditions. In the latest experimental campaign in 2018, increases to 55.4 A with the averaged current density being 233 A m−2 for 1.5 s using the shot extraction gap length. The low of 0.31 can be maintained by using high discharge power. The various parameters mentioned above are defined in detail below

Extension of high power deuterium operation of negative ion based neutral beam injector in the large helical device

Second deuterium operation of the negative ion based neutral beam injector was performed in 2018 in the large helical device. The electron and ion current ratio improves to Ie/Iacc(D) = 0.31 using the short extraction gap distance of 7 mm between the plasma grid (PG) and the extraction grid (EG). The strength of the magnetic field by the electron deflection magnet installed in the EG increases by 17% at the PG ingress surface, which effectively reduces the electron component in the negative ion rich plasma in the vicinity of PG apertures. The reduction of the electron current made it possible to operate at a high power arc discharge and beam extraction. Then, the deuterium negative ion current increases to 55.4 A with the averaged current density of 233 A/m2. The thermal load on the EG using 7 mm gap distance is 0.6 times smaller than the thermal load using a 8 mm gap caused by the reduction of coextracted electron current. The injection beam power increases to 2.9 MW in the beam line BL3, and the total beam injection power increases to 7 MW by three beam lines in the second deuterium campaign

A combination of routine laboratory findings and vital signs can predict survival of advanced cancer patients without physician evaluation: a fractional polynomial model

IntroductionThere have been no reports about predicting survival of patients with advanced cancer constructed entirely with objective variables. We aimed to develop a prognostic model based on laboratory findings and vital signs using a fractional polynomial (FP) model.MethodsA multicentre prospective cohort study was conducted at 58 specialist palliative care services in Japan from September 2012 to April 2014. Eligible patients were older than 20 years and had advanced cancer. We developed models for predicting 7-day, 14-day, 30-day, 56-day and 90-day survival by using the FP modelling method.ResultsData from 1039 patients were analysed to develop each prognostic model (Objective Prognostic Index for advanced cancer [OPI-AC]). All models included the heart rate, urea and albumin, while some models included the respiratory rate, creatinine, C-reactive protein, lymphocyte count, neutrophil count, total bilirubin, lactate dehydrogenase and platelet/lymphocyte ratio. The area under the curve was 0.77, 0.81, 0.90, 0.90 and 0.92 for the 7-day, 14-day, 30-day, 56-day and 90-day model, respectively. The accuracy of the OPI-AC predicting 30-day, 56-day and 90-day survival was significantly higher than that of the Palliative Prognostic Score or the Prognosis in Palliative Care Study model, which are based on a combination of symptoms and physician estimation.ConclusionWe developed highly accurate prognostic indexes for predicting the survival of patients with advanced cancer from objective variables alone, which may be useful for end-of-life management. The FP modelling method could be promising for developing other prognostic models in future research

Carbon impurities behavior and its impact on ion thermal confinement in high-ion-temperature deuterium discharges on the Large Helical Device

The behavior of carbon impurities in deuterium plasmas and its impact on thermal confinement were investigated in comparison with hydrogen plasmas in the Large Helical Device (LHD). Deuterium plasma experiments have been started in the LHD and high-ion-temperature plasmas with central ion temperature (T i) of 10 keV were successfully obtained. The thermal confinement improvement could be sustained for a longer time compared with hydrogen plasmas. An isotope effect was observed in the time evolution of the carbon density profiles. A transiently peaked profile was observed in the deuterium plasmas due to the smaller carbon convection velocity and diffusivity in the deuterium plasmas compared with the hydrogen plasmas. The peaked carbon density profile was strongly correlated to the ion thermal confinement improvement. The peaking of the carbon density profile will be one of the clues to clarify the unexplained mechanisms for the formations of ion internal transport barrier and impurity hole on LHD. These results could also lead to a better understanding of the isotope effect in the thermal confinement in torus plasma

The isotope effect on impurities and bulk ion particle transport in the Large Helical Device

The isotope effect on impurities and bulk ion particle transport is investigated by using the deuterium, hydrogen, and isotope mixture plasma in the Large Helical Device (LHD). A clear isotope effect is observed in the impurity transport but not the bulk ion transport. The isotope effects on impurity transport and ion heat transport are observed as a primary and a secondary effect, respectively, in the plasma with an internal transport barrier (ITB). In the LHD, an ion ITB is always transient because the impurity hole triggered by the increase of ion temperature gradient causes the enhancement of ion heat transport and gradually terminates the ion ITB. The formation of an impurity hole becomes slower in the deuterium (D) plasma than the hydrogen (H) plasma. This primary isotope effect on impurity transport contributes the longer sustainment of the ion ITB state because the low ion thermal diffusivity can be sustained as long as the normalized carbon impurity gradient R/Ln,c, where , is above the critical value (~−5). Therefore, the longer sustainment of the ITB state in the deuterium plasma is considered to be a secondary isotope effect due to the mitigation of the impurity hole. The radial profile of H and D ion density is measured using bulk charge exchange spectroscopy inside the isotope mixture plasma. The decay time of H ion density after the H-pellet injection and the decay time of D ion density after D-pellet injection are almost identical, which demonstrates that there is no significant isotope effect on ion particle transport

Collaborative Virtual Screening Identifies a 2-Aryl-4-aminoquinazoline Series with Efficacy in an In Vivo Model of Trypanosoma cruzi Infection

Probing multiple proprietary pharmaceutical libraries in parallel via virtual screening allowed rapid expansion of the structure-activity relationship (SAR) around hit compounds with moderate efficacy against Trypanosoma cruzi, the causative agent of Chagas Disease. A potency-improving scaffold hop, followed by elaboration of the SAR via design guided by the output of the phenotypic virtual screening efforts, identified two promising hit compounds 54 and 85, which were profiled further in pharmacokinetic studies and in an in vivo model of T. cruzi infection. Compound 85 demonstrated clear reduction of parasitemia in the in vivo setting, confirming the interest in this series of 2-(pyridin-2-yl)quinazolines as potential anti-trypanosome treatments