A nationwide randomized, double-blind, placebo-controlled physicians’ trial of loxoprofen for the treatment of fatigue, headache, and nausea after hangovers

Hangovers are associated with negative economic consequences due to decreased job performance or frequent visits to physicians. Thus, a new strategy for the alleviation of hangover-related symptoms is needed to avoid this detriment to society. The purpose of this nationwide randomized, double-blind, placebo-controlled physicians’ trial was to evaluate the efficacy of loxoprofen sodium for the alleviation of fatigue, headache, and nausea after hangover. A total of 229 participants were randomized to receive loxoprofen sodium (60 mg once orally) or placebo. The study was closed when the first 150 participants (n = 74 in the loxoprofen vs. n = 76 in the placebo groups) experienced hangovers. The primary endpoint was set as the difference in severity of general fatigue before and 3 h after taking the test drugs and was evaluated using a visual analogue scale. Secondary endpoints included difference in severity of headache, nausea, and incidence of adverse events. The study participants were 34 (interquartile range; 30-39) years old, 92.0% were men, and both groups were comparable for baseline characteristics. The alleviation of general fatigue did not differ statistically between the loxoprofen and placebo groups (24 [14-49] vs. 19 [9-35], p = 0.07). However, the alleviation of headache was statistically greater in the loxoprofen group (25 [10-50] vs. 10 [2-30], adjusted difference 14, 95% confidence interval 8-21, p < 0.001), whereas, there was no difference in nausea (7 [0-27] vs. 10 [0-24], p = 0.68). The incidence of adverse symptoms such as epigastric discomfort was also comparable between groups (2.7% vs. 3.9%, p = 0.25). Loxoprofen sodium was effective for relieving headaches after hangovers but did not alleviate general fatigue or nausea.Masahiko Hara, Kenichi Hayashi, Tetsuhisa Kitamura, Michitaka Honda, Masatake Tamaki, A nationwide randomized, double-blind, placebo-controlled physicians’ trial of loxoprofen for the treatment of fatigue, headache, and nausea after hangovers, Alcohol, Volume 84, 2020, Pages 21-25, ISSN 0741-8329, https://doi.org/10.1016/j.alcohol.2019.10.006

Design space exploration of low-phase-noise LC-VCO using multiple-divide technique

Abstract — This paper proposes a multiple-divide technique using by-2, by-3, and by-4 frequency dividers to realize a lower phase-noise LC-VCO, and explores the design space of low-phase-noise VCO using the multiple-divide technique. In the simulated results using 90-nm CMOS model parameters, the optimum frequency range, achieving better than ¡191 dBc/Hz of FoM, can be extended from 6-12 GHz to 1.5-12 GHz. I

Diacylglycerol Kinase β Knockout Mice Exhibit Attention-Deficit Behavior and an Abnormal Response on Methylphenidate-Induced Hyperactivity

BACKGROUND: Diacylglycerol kinase (DGK) is an enzyme that phosphorylates diacylglycerol to produce phosphatidic acid. DGKβ is one of the subtypes of the DGK family and regulates many intracellular signaling pathways in the central nervous system. Previously, we demonstrated that DGKβ knockout (KO) mice showed various dysfunctions of higher brain function, such as cognitive impairment (with lower spine density), hyperactivity, reduced anxiety, and careless behavior. In the present study, we conducted further tests on DGKβ KO mice in order to investigate the function of DGKβ in the central nervous system, especially in the pathophysiology of attention deficit hyperactivity disorder (ADHD). METHODOLOGY/PRINCIPAL FINDINGS: DGKβ KO mice showed attention-deficit behavior in the object-based attention test and it was ameliorated by methylphenidate (MPH, 30 mg/kg, i.p.). In the open field test, DGKβ KO mice displayed a decreased response to the locomotor stimulating effects of MPH (30 mg/kg, i.p.), but showed a similar response to an N-methyl-d-aspartate (NMDA) receptor antagonist, MK-801 (0.3 mg/kg, i.p.), when compared to WT mice. Examination of the phosphorylation of extracellular signal-regulated kinase (ERK), which is involved in regulation of locomotor activity, indicated that ERK1/2 activation induced by MPH treatment was defective in the striatum of DGKβ KO mice. CONCLUSIONS/SIGNIFICANCE: These findings suggest that DGKβ KO mice showed attention-deficit and hyperactive phenotype, similar to ADHD. Furthermore, the hyporesponsiveness of DGKβ KO mice to MPH was due to dysregulation of ERK phosphorylation, and that DGKβ has a pivotal involvement in ERK regulation in the striatum

High Excess Risk of Heart Disease Mortality among Hiroshima Atomic Bomb Male Survivors Exposed Near the Hypocenter

Heart disease (HD) mortality is the second leading cause of death in Japan. The HD mortality risk among Atomic bomb survivors is slightly positive but shows a statistically significant dose-response relationship with initial radiation dose, as reported by the Radiation Effects Research Foundation. In that report, dosimetry was based on initial radiation only, with the effect of indirect radiation dose not taken into consideration. The atomic bomb radiation, however, consisted of both initial and residual radiation. We reevaluated the dose-response relationship for HD mortality using exposure distance (ground distance between the location where exposed and the hypocenter) as a surrogate indicator of radiation dose. At Hiroshima University, a cohort study has been conducted with Hiroshima Atomic Bomb Survivors (ABS) since 1970. We selected 29605 subjects from the ABS who were exposed at 3.5 km or less from the hypocenter and alive on January 1, 1970. These subjects, referred to as “Hiroshima hibakusha” in this paper, were followed until December 31, 2010. We stratified the cohort data with respect to sex and age at the time of bombing (ATB) into 10-year age groups. For each stratum, by applying an extended Cox regression model with time-dependent covariates, we analyzed the risk of HD mortality using either initial radiation dose or exposure distance as an explanatory variable. The results indicate a high excess risk in males and older age ATB females who were exposed near the hypocenter. This difference may be explained by the effect of female sex hormone on the circulatory system among young age ATB females. Some unknown risk factor related to exposure distance was also implicated in the elevated risk of HD among the Hiroshima hibakusha, especially in males. This necessitates further study.This research was supported in part by Grants-in-Aid for Scientific Research (A) 24249039 (2012–2014), and the Joint Usage/Research Center (RIRBM), Hiroshima University

The role of a group III AQP, AQP11 in intracellular organelle homeostasis

AQP11 is a member of a new aquaporin subfamily which includes many aquaporin homologs with low amino acid identities, around 20% of previously identified AQPs. Although these AQPs have unusual NPA sequences, these AQPs have a completely conserved and functionally indispensable cysteine residue downstream of the second NPA box, suggesting that they belong to a specific AQP subfamily, which we propose to name the group III AQPs. On the other hand, the NPA boxes are highly conserved in previous AQP subfamilies : the group I AQPs, original water-selective aquaporin family and the group II AQPs, aquaglyceroporin family. Currently the roles of the group III AQPs are only known with AQP11 as the disruption of intracellularly located AQP11 in mice produced huge vacuoles in the proximal tubule leading to fatal polycystic kidneys at one month old. This review focused on the classification of AQPs based on primary structures to obtain insights into the function and the role of AQPs. With the accumulation of new AQP-like sequences through genome projects, this classification will be useful to predict their functions as each group may have specific characteristics in its function, distribution and regulation

Monitoring serum IL-18 levels is useful for treatment of a patient with systemic juvenile idiopathic arthritis complicated by macrophage activation syndrome

Systemic juvenile idiopathic arthritis (sJIA) is a systemic inflammatory disease characterized by arthritis, spiking fever and a skin rash that is frequently complicated by macrophage activation syndrome (MAS), a life-threatening disorder. We report a 22-month-old girl with sJIA who developed severe MAS but was successfully treated with corticosteroids, cyclosporin A, and non-steroidal anti-inflammatory drugs by monitoring serum IL-18 levels. IL-18 is an extremely useful cytokine for monitoring the activity of sJIA and MAS, and serum IL-18 can be used as an indicator for the effectiveness of treatment and the decision to discontinue therapy.ArticlePEDIATRIC RHEUMATOLOGY. 9:15 (2011)journal articl

Pembrolizumab-induced hypothyroidism caused reversible increased serum creatinine levels: a case report

Background The advent of immune checkpoint inhibitors (ICIs) has significantly improved the prognosis of patients with advanced malignancies. On the other hand, these drugs might cause immune-related adverse events (irAEs) including endocrinopathies and nephropathies. Thyroid dysfunction is one of the most common irAEs. For ICIs-induced nephropathies, most cases are due to tubulointerstitial nephritis, which might require steroid treatment. Here, we report a patient with non-small cell lung cancer treated with ICI who developed increased serum creatinine (s-Cr) levels due to ICIs-induced hypothyroidism. Case presentation A 57-year-old Asian man with refractory non-small cell lung cancer under ICIs therapy (pembrolizumab, an anti-programmed cell death-1 monoclonal antibody) developed increased s-Cr levels 5 months after the pembrolizumab initiation. His laboratory data, renal biopsy, and Gallium-67 scintigraphy findings denied pembrolizumab-induced tubulointerstitial nephritis. His renal function was correlated with thyroid function. Despite the increase of s-Cr levels, serum cystatin C levels were normal, which could be explained by the hypothyroidism. Levothyroxine treatment improved renal function as well as thyroid function. Then pembrolizumab was resumed, and both his thyroid and renal function remained normal level. Ultimately, we concluded that the increased s-Cr levels were caused by pembrolizumab-induced hypothyroidism. Conclusion All clinicians involved in ICI treatment need to recognize the possible increase in s-Cr levels caused by ICIs-induced hypothyroidism, and we propose monitoring serum cystatin C levels to differentiate ICIs-induced hypothyroidism from tubulointerstitial nephritis before invasive renal biopsies or steroid treatment, which are recommended by the prescribing information for pembrolizumab, are performed

Effects of Wnt-β-Catenin Signaling and Sclerostin on the Phenotypes of Rat Pheochromocytoma PC12 Cells

Pheochromocytomas and paragangliomas (PPGLs) are classified into 3 major categories with distinct driver genes: pseudohypoxia, kinase signaling, and Wnt-altered subtypes. PPGLs in the Wnt-altered subtype are sporadic and tend to be aggressive with metastasis, where somatic gene fusions affecting mastermind-like 3 (MAML3) and somatic mutations in cold shock domain containing E1 (CSDE1) cause overactivation of Wnt-β-catenin signaling. However, the relation between Wnt-β-catenin signaling and the biological behavior of PPGLs remains unexplored. In rat pheochromocytoma PC12 cells, Wnt3a treatment enhanced cell proliferation and suppressed mRNA expression of tyrosine hydroxylase (TH), the rate-limiting enzyme of catecholamine biosynthesis, and dopamine secretion. We identified the expression of sclerostin in PC12 cells, which is known as an osteocyte-derived negative regulator for Wnt signaling-driven bone formation. Inhibition of endogenous Wnt pathway by XAV939 or sclerostin resulted in attenuated cell proliferation and increased TH expression. Furthermore, Wnt3a pretreatment suppressed bone morphogenetic protein (BMP)-induced Smad1/5/9 phosphorylation whereas BMPs enhanced sclerostin expression in PC12 cells. In the Wnt-altered subtype, the increased Wnt-β-catenin pathway may contribute the aggressive clinical behavior with reduced catecholamine production. Furthermore, upregulated expression of sclerostin by BMPs may explain the osteolytic metastatic lesions observed in metastatic PPGLs