Effects of the Coronavirus disease 2019 pandemic on mortality in patients with lung cancer: A multiple mediation analysis in Japan.

COVID-19 pandemic has had a substantial effect on healthcare systems worldwide, including the care of patients with lung cancer. The impact of healthcare disruptions and behavioral changes on lung cancer mortality is unclear. Patients newly diagnosed with lung cancer during the pandemic period 2020-2021 were compared with those diagnosed in the pre-pandemic 2018-2019. The primary outcome was all-cause mortality within 1 year. Cox proportional hazards regression analyses were conducted to estimate the changes in mortality between pandemic and pre-pandemic. Multiple mediation analyses were performed to determine the factors that accounted for the changes in mortality. In total, 5785 patients with lung cancer were included in this study. The overall mortality rate was significantly higher during the pandemic compared with the pre-pandemic (crude hazard ratio [HR]: 1.19, 95% confidence interval [CI]: 1.05, 1.29). Mediation analyses showed that not receiving tumor-directed treatment, diagnosis at an older age, and decreased diagnosis through cancer screening significantly accounted for 17.5% (95%CI: 4.2, 30.7), 13.9% (95%CI: 0.8, 27.0), and 12.4% (95%CI: 3.0, 21.8) of the increased mortality, respectively. This study revealed a significant increase in mortality risk in patients with lung cancer who have not received tumor-directed treatment or cancer screening, despite potential selection bias for follow-up status. Efforts should be focused on ensuring timely access to healthcare services, optimizing treatment delivery, and addressing the unique challenges faced by patients with lung cancer during the pandemic to mitigate the impact of the pandemic on lung cancer outcomes and provide clinical care to vulnerable populations.

A Behavioral and Electroencephalographic Study of Anesthetic State Induced by MK-801 Combined with Haloperidol, Ketamine and Riluzole in Mice.

BACKGROUND: Ketamine is an intravenous anesthetic that acts as a channel blocker on the N-methyl- d -aspartate (NMDA) receptor, a glutamate receptor subtype. MK-801 is the most potent compound among noncompetitive NMDA receptor antagonists. Ketamine induces loss of the righting reflex (LORR) in rodents, which is one of the indicators of unconsciousness, whereas high doses of MK-801 produce ataxia, but not LORR. In contrast, we previously reported that MK-801 combined with a low dose of the dopamine receptor antagonist haloperidol-induced LORR in mice. To assess a neurophysiologically distinct brain state and demonstrate unconsciousness, electroencephalograms (EEG) need to be examined together with LORR. Therefore, we herein investigated EEG changes after the systemic administration of MK-801 alone or in combination with haloperidol, and compared them with those induced by ketamine, the glutamate release inhibitor riluzole, and the γ-aminobutyric acid type A receptor agonist propofol. METHODS: All drugs were intraperitoneally administered to adult male ddY mice (n = 168). General anesthesia was evaluated based on the righting reflex test. Animals who exhibited no righting for more than 30 seconds were considered to have LORR. In a separate group of mice, EEG of the primary visual cortex was recorded before and after the administration of MK-801 (3.0 mg/kg) alone or in combination with haloperidol (0.2 mg/kg), ketamine (150 mg/kg), riluzole (30 mg/kg), or propofol (240 mg/kg). The waveforms recorded were analyzed using EEG power spectra and spectrograms. RESULTS: The high dose of MK-801 alone did not induce LORR, whereas MK-801 combined with haloperidol produced LORR in a dose-dependent manner. Ketamine, riluzole, and propofol also dose-dependently induced LORR. In the EEG study, MK-801 alone induced a significant increase in δ power, while MK-801 plus haloperidol exerted similar effects on not only δ, but also θ and α power during LORR, suggesting that increases in δ, θ, and α power were necessary for LORR. The results obtained on MK-801 plus haloperidol were similar to those on ketamine in the behavioral and EEG studies, except for an increase in γ power by ketamine during LORR. Propofol significantly increased δ, θ, α, and ß power during LORR. However, the EEG results obtained using riluzole, which produced a unique pattern of lower amplitude activity spanning most frequencies, markedly differed from those with the other drugs. CONCLUSIONS: This study revealed differences in EEG changes induced by various sedatives. The results obtained on MK-801 alone and MK-801 plus haloperidol suggest the importance of dopamine transmission in maintaining the righting reflex.

Randomized open-label study of second-generation antipsychotics for the treatment of schizophrenia: 104-week final results of the JUMPs study assessing treatment discontinuation, remission, and social functioning.

BACKGROUND: We report the final results of treatment with aripiprazole, blonanserin, and paliperidone from the Japan Useful Medication Program for Schizophrenia (JUMPs), a 104-week naturalistic study. METHODS: JUMPs was an open-label, three-arm, randomized, parallel-group, 104-week study. Patients aged ≥ 20 years with schizophrenia requiring antipsychotic treatment or a switch from previous therapy were enrolled. The primary endpoint was treatment discontinuation rate over 104 weeks. Secondary endpoints included remission rate, Personal and Social Performance (PSP), safety, Positive and Negative Syndrome Scale (PANSS), and quality of life (QOL; EuroQol-5 dimension). RESULTS: In total, 251 patients received aripiprazole (n = 82), blonanserin (n = 85), or paliperidone (n = 84). Treatment discontinuation rates (aripiprazole, 80.5%; blonanserin, 81.2%; paliperidone, 71.4%) were not significantly different (p = 0.2385) among the treatment groups at 104 weeks; comparable outcomes were observed for endpoints, including remission (42.9%, 46.7%, and 45.8%), PANSS, and safety. In the overall cohort, while the improvement in the PSP total score at Week 104 was not significantly different from baseline, a significant improvement (p < 0.05) in QOL and total PANSS scores (including all subscales) was observed at Week 104 compared with baseline. Multivariable analysis identified a shorter disease duration and a higher chlorpromazine-equivalent antipsychotic dosage level (≥ 1000 mg) before switching to monotherapy as predictors of treatment discontinuation. CONCLUSIONS: The 104-week treatment outcomes were comparable between groups; the overall trend of improvement in remission rate, safety, and QOL suggests the importance of continued treatment. CLINICAL TRIAL REGISTRATION: UMIN-Clinical Trials Registry UMIN000007942 (public release date: 14/05/2012).

Impact of home visiting nurses on home death proportion in Japan: A nationwide longitudinal ecological study.

OBJECTIVE: Home visiting nurses contribute to end-of-life home care in an aging society. However, few previous studies reported patient outcomes based on nursing practices. This study aimed to examine the correlation between the number of them and the change in home death proportion. METHODS: We divided the number of home visiting nurses into four categories: absent, shortage, medium, and abundant. This study adopted the interaction term between the nurse categories and year as the major exposure variable, and home death proportion per municipality as the objective variable. We estimated the average marginal effects (AME) as the change in home death proportion from 2015 to 2020. RESULTS: The total number of home visiting nurses was 36,483 in 2015 and 65,868 in 2020. The coefficients of the interaction term were statistically significant in medium and abundant municipalities (Medium: 1.26 (95% CI: 0.49-2.04), Abundant: 2.15 (95% CI: 0.76-3.55)). Increased home death proportion were estimated as AME: 1.56% (95% CI: 0.99-2.13), 1.35% (95% CI: 0.85-1.84), 2.82% (95% CI: 2.30-3.35), and 3.71% (95% CI: 2.44-4.99) in the absent, shortage, medium, and abundant areas, respectively. CONCLUSIONS: To increase the proportion of home deaths, municipalities require a certain number of home visiting nurses.

Discontinuation and remission rates and social functioning in patients with schizophrenia receiving second-generation antipsychotics: 52-week evaluation of JUMPs, a randomized, open-label study.

AIM: Globally, evidence from short-term studies is insufficient for the guidelines to uniformly recommend a particular antipsychotic(s) for the maintenance treatment of schizophrenia. Therefore, long-term comprehensive evaluation of antipsychotics is required from a social rehabilitation perspective, especially for drugs that have not yet been studied. The Japan Useful Medication Program for Schizophrenia (JUMPs) is a large-scale, long-term naturalistic study to present pivotal 52-week data on the continuity of second-generation antipsychotics (SGA: aripiprazole, blonanserin, and paliperidone). METHODS: JUMPs was an open-label, three-arm, randomized, parallel-group, 52-week study. Enrolled patients had schizophrenia, were ≥20 years old, and required antipsychotic treatment or switched from previous therapy. The primary endpoint was treatment discontinuation rate over 52 weeks. Secondary outcomes included remission rate, social functioning, and quality-of-life scores [Personal and Social Performance Scale (PSP) and EuroQol-5 dimensions], and safety. RESULTS: In total, 251 patients received aripiprazole (n = 82), blonanserin (n = 85), or paliperidone (n = 84). The discontinuation rate (P = 0.9771) and remission rates (P > 0.05) over 52 weeks did not differ significantly between the three treatment groups. The discontinuation rates were 68.3%, 68.2%, and 65.5% in the aripiprazole, blonanserin, and paliperidone groups, respectively. Significant improvements (all P < 0.05) from baseline in PSP scores were observed at start of monotherapy, week 26, and week 52 in the overall cohort and blonanserin group and at week 26 in the aripiprazole group. The adverse event profile favored blonanserin. CONCLUSION: All three SGAs evaluated in this study showed similar treatment discontinuation rates in patients with chronic schizophrenia in Japan.

Pharmacological Treatment of Schizophrenia: Japanese Expert Consensus.

INTRODUCTION: Conventional treatment guidelines of schizophrenia do not necessarily provide solutions on clinically important issues. METHODS: A total of 141 certified psychiatrists of the Japanese Society of Clinical Neuropsychopharmacology evaluated treatment options regarding 19 clinically relevant situations in the treatment of schizophrenia with a 9-point scale (1="disagree" and 9="agree"). RESULTS: First-line antipsychotics varied depending on predominant symptoms: risperidone (mean±standard deviation score, 7.9±1.4), olanzapine (7.5±1.6), and aripiprazole (6.9±1.9) were more likely selected for positive symptoms; aripiprazole (7.6±1.6) for negative symptoms; aripiprazole (7.3±1.9), olanzapine (7.2±1.9), and quetiapine (6.9±1.9) for depression and anxiety; and olanzapine (7.9±1.5) and risperidone (7.5±1.5) for excitement and aggression. While only aripiprazole was categorized as a first-line treatment for relapse prevention (7.6±1.0) in patients without noticeable symptoms, aripiprazole (8.0±1.6) and brexpiprazole (6.9±2.3) were categorized as such for social integration. First-line treatments in patients who are vulnerable to extrapyramidal symptoms include quetiapine (7.5±2.0) and aripiprazole (6.9±2.1). DISCUSSION: These clinical recommendations represent the expert consensus on the use of a particular antipsychotic medication for a particular situation, filling a current gap in the literature.

Variation of vortex veins at the horizontal watershed in normal eyes.

PURPOSE: To assess the vascular pattern of choroidal vortex veins at the horizontal watershed zone in normal eyes using optical coherence tomography (OCT). METHODS: We retrospectively studied 207 normal eyes of 207 patients whose fellow eyes were diagnosed with unilateral retinal diseases without choroidal involvement. Venous anastomosis between the superior and inferior vortex veins and deviation of the horizontal watershed zone were evaluated using 12 × 12-mm en face OCT images. Central choroidal thickness (CCT) was measured on B-mode OCT images. RESULTS: Vortex vein anastomosis was observed in 92 eyes (44.4%) at the horizontal watershed zone. Superior or inferior deviation of the horizontal watershed was ascertained in 69 eyes (33.3%). The frequency of the anastomosis and deviation did not differ significantly between age groups (P = 0.56 and 0.96, respectively). Mean CCT of all eyes was 221 ± 80 µm. CCT was significantly greater in eyes with anastomosis than in those without (233 ± 73 µm vs 210 ± 83 µm, P < 0.05). However, CCT did not differ significantly between eyes with and without deviation of the horizontal watershed zone (223 ± 74 µm vs 219 ± 82 µm). CONCLUSIONS: Venous anastomosis at the horizontal watershed zone as well as superior or inferior deviation of the zone were frequently observed in normal eyes. CCT was greater in eyes with than in those without anastomosis, suggesting subclinical vortex vein congestion.

Effects on monotherapy and reduction of antipsychotic drugs by clozapine therapy in Japanese patients with treatment-resistant schizophrenia.

WHAT IS KNOWN AND OBJECTIVE: The schizophrenia guidelines in Japan and many other countries describe clozapine as the first-choice drug for patients with treatment-resistant schizophrenia. However, there have been no reports to date on the effects of the introduction of clozapine on the prescription of other antipsychotics and concomitant drugs. METHODS: In this study, we retrospectively investigated the prescription of antipsychotics and concomitant drugs before vs 6 months after and 12 months after switching to clozapine. RESULTS AND DISCUSSION: Clozapine was introduced to 62 patients with treatment-resistant schizophrenia, and 51 patients continued on clozapine therapy. Six months after switching to clozapine, there was a significant decrease in the mean number of antipsychotic drugs (2.04 ± 0.75 vs 1.10 ± 0.30: p < 0.001) and in the mean chlorpromazine equivalent value (1024 ± 73 mg/day vs 781 ± 391 mg/day: p < 0.001) compared to before switching. Moreover, antipsychotic monotherapy increased from 24% to 90% after switching to clozapine. In addition, the number of concomitant benzodiazepines, anti-parkinson drugs and antidepressants also significantly decreased 6 and 12 months after switching to clozapine (p < 0.001 for benzodiazepines and anti-parkinson drugs, and p < 0.05 for antidepressants). WHAT IS NEW AND CONCLUSION: Our study suggests that switching to clozapine may reduce the use of antipsychotic combination therapy, and may also reduce the number of concomitant drugs.

Virtual Interpolation Images of Tumor Development and Growth on Breast Ultrasound Image Synthesis With Deep Convolutional Generative Adversarial Networks.

OBJECTIVES: We sought to generate realistic synthetic breast ultrasound images and express virtual interpolation images of tumors using a deep convolutional generative adversarial network (DCGAN). METHODS: After retrospective selection of breast ultrasound images of 528 benign masses, 529 malignant masses, and 583 normal breasts, 20 synthesized images of each were generated by the DCGAN. Fifteen virtual interpolation images of tumors were generated by changing the value of the input vector. A total of 60 synthesized images and 20 virtual interpolation images were evaluated by 2 readers, who scored them on a 5-point scale (1, very good; to 5, very poor) and then answered whether the synthesized image was benign, malignant, or normal. RESULTS: The mean score of overall quality for synthesized images was 3.05, and that of the reality of virtual interpolation images was 2.53. The readers classified the generated images with a correct answer rate of 92.5%. CONCLUSIONS: A DCGAN can generate high-quality synthetic breast ultrasound images of each pathologic tissue and has the potential to create realistic virtual interpolation images of tumor development.

An Artificial Z-Scheme Constructed from Dye-Sensitized Metal Oxide Nanosheets for Visible Light-Driven Overall Water Splitting.

Sensitization of a wide-gap oxide semiconductor with a visible-light-absorbing dye has been studied for decades as a means of producing H2 from water. However, efficient overall water splitting using a dye-sensitized oxide photocatalyst has remained an unmet challenge. Here we demonstrate visible-light-driven overall water splitting into H2 and O2 using HCa2Nb3O10 nanosheets sensitized by a Ru(II) tris-diimine type photosensitizer, in combination with a WO3-based water oxidation photocatalyst and a triiodide/iodide redox couple. With the use of Pt-intercalated HCa2Nb3O10 nanosheets further modified with amorphous Al2O3 clusters as the H2 evolution component, the dye-based turnover number and frequency for H2 evolution reached 4580 and 1960 h-1, respectively. The apparent quantum yield for overall water splitting using 420 nm light was 2.4%, by far the highest among dye-sensitized overall water splitting systems reported to date. The present work clearly shows that a carefully designed dye/oxide hybrid has great potential for photocatalytic H2 production, and represents a significant leap forward in the development of solar-driven water splitting systems.

Pharmacological management of bipolar disorder: Japanese expert consensus.

OBJECTIVES: The aim of this study was to develop a consensus guideline by certified experts of the Japanese Society of Clinical Neuropsychopharmacology on the psychopharmacological treatment for bipolar disorders I and II (BP-I and BP-II), in order to fill the gap in the literature and provide more concrete guidance for challenging and controversial real-world situations. METHODS: Experts were asked to assess treatment options regarding 19 clinical situations of bipolar disorder with a nine-point Likert scale (one = "disagree" and nine = "agree"). According to the responses from 119 experts, the options were categorized into the first-, second-, and third-line treatments. RESULTS: For the treatment of BP-I, lithium monotherapy was categorized as a first-line treatment for manic episodes (mean ± standard deviation score, 7.0 ± 2.2), depressive episodes (7.1 ± 2.0), and the maintenance phase (7.8 ± 1.8). Combination therapy of lithium and an atypical antipsychotic was endorsed for manic episodes (7.7 ± 1.7), depressive episodes with (7.1 ± 2.0) and without mixed features (6.9 ± 2.2), and the maintenance phase (6.9 ± 2.1). Similarly, in BP-II, lithium monotherapy was categorized as a first-line treatment for hypomanic episodes (7.3 ± 2.2), depressive episodes (7.0 ± 2.2), and the maintenance phase (7.3 ± 2.3), while combination therapy of lithium and an atypical antipsychotic was recommended for hypomanic episodes (6.9 ± 2.4).No antipsychotic monotherapy or antidepressant treatment was categorized as a first-line treatment for any type of episode. CONCLUSIONS: These recommendations reflect the current evidence and represent the experts' consensus on using lithium for the treatment of bipolar disorder. Clinicians should consider the effectiveness and adverse effects of antipsychotic and antidepressant medications for the treatment of bipolar disorder.

Classification of Breast Masses on Ultrasound Shear Wave Elastography using Convolutional Neural Networks.

We aimed to use deep learning with convolutional neural networks (CNNs) to discriminate images of benign and malignant breast masses on ultrasound shear wave elastography (SWE). We retrospectively gathered 158 images of benign masses and 146 images of malignant masses as training data for SWE. A deep learning model was constructed using several CNN architectures (Xception, InceptionV3, InceptionResNetV2, DenseNet121, DenseNet169, and NASNetMobile) with 50, 100, and 200 epochs. We analyzed SWE images of 38 benign masses and 35 malignant masses as test data. Two radiologists interpreted these test data through a consensus reading using a 5-point visual color assessment (SWEc) and the mean elasticity value (in kPa) (SWEe). Sensitivity, specificity, and area under the receiver operating characteristic curve (AUC) were calculated. The best CNN model (which was DenseNet169 with 100 epochs), SWEc, and SWEe had a sensitivity of 0.857, 0.829, and 0.914 and a specificity of 0.789, 0.737, and 0.763 respectively. The CNNs exhibited a mean AUC of 0.870 (range, 0.844-0.898), and SWEc and SWEe had an AUC of 0.821 and 0.855. The CNNs had an equal or better diagnostic performance compared with radiologist readings. DenseNet169 with 100 epochs, Xception with 50 epochs, and Xception with 100 epochs had a better diagnostic performance compared with SWEc (P = 0.018-0.037). Deep learning with CNNs exhibited equal or higher AUC compared with radiologists when discriminating benign from malignant breast masses on ultrasound SWE.

Small spheroids of adipose-derived stem cells with time-dependent enhancement of IL-8 and VEGF-A secretion.

Wound-healing factors secreted from mesenchymal stem cells (MSCs) modulate the immune response and facilitate proliferation of neighboring cells. Although in vitro three-dimensional (3D) culture techniques have improved the therapeutic potential of MSCs, no studies have focused on the effects of cell aggregation alone. In this study, the effect of cell aggregation on the up-regulation of wound-healing proteins secretions was investigated by constructing small spheroids of human adipose-derived stem cells (hADSCs) on a micropatterned surface. These spheroids were mostly unaffected by the secondary effects of cell aggregation, such as hypoxia, low-nutrient supply, and metabolic waste accumulation. Small spheroids of hADSCs, which were of 100 µm in diameter, were successfully constructed using micropatterned surface. Expression of the wound-healing-related factors, VEGF-A and IL-8, was markedly enhanced at the gene and protein levels, whereas the enhancement of VEGF-A expression was transient and IL-8 enhancement was maintained for a long time.

Assessing the Influence of the COVID-19 Pandemic on Gastric Cancer Mortality Risk.

BACKGROUND: The global impact of the coronavirus disease 2019 (COVID-19) pandemic on public health has been significant. Upper gastrointestinal endoscopy for screening and diagnosis decreased along with new gastric cancer (GC) diagnoses. METHODS: This study assesses how the pandemic affected GC mortality using data from Hiroshima Prefecture, comparing mortality rates between patients diagnosed during the pandemic (2020 and 2021) and pre-pandemic (2018 and 2019) periods. The crude hazard ratios (HRs) and HRs adjusted for age, sex, clinical stage, treatment status, and travel distance to the nearest GC screening facility were estimated using Cox regression models. Subgroup and sensitivity analyses were also performed. RESULTS: A total of 9571 patients were diagnosed, with 4877 eligible for follow-up. The median age was 74 years, and 69% were male. The median follow-up period was 157 days, with events per 1000 person-years at 278 and 374 in the pre-pandemic and pandemic periods, respectively (crude HR, 1.37; adjusted HR, 1.17). The sensitivity and subgroup analyses yielded consistent results. CONCLUSIONS: The COVID-19 pandemic increased mortality risk in patients with GC. Further studies are required to observe long-term outcomes and identify the disparities contributing to the increased mortality risk.

Impact of the COVID-19 pandemic on the mortality among patients with colorectal cancer in Hiroshima, Japan: A large cancer registry study.

BACKGROUND: This retrospective cohort study aimed to evaluate the impact of the COVID-19 pandemic on colorectal cancer care and mortality using a large cancer registry in Hiroshima Prefecture, Japan. The study aimed to estimate the all-cause mortality rates within 1 year of diagnosis among colorectal cancer patients diagnosed during the pandemic period (2020 and 2021) compared to those diagnosed during the pre-pandemic period (2018 and 2019). METHODS: The day of diagnosis was set as Day 0 and Cox regression models were utilized to estimate crude hazard ratios (HRs) and adjusted HRs, accounting for age, sex, cancer stage, and treatment status. Two sensitivity analyses of overall survival were performed with different cutoffs of the pre-pandemic/pandemic periods and year-to-year comparisons. Subgroup analyses were performed using likelihood ratio tests. RESULTS: A total of 15,085 colorectal cancer patients were included, with 6499 eligible for follow-up. A median age of included patients was 72 years old, of which 59% were male. The distribution of cancer stages showed little variation between the pre-pandemic and pandemic periods. With a median follow-up of 177 days, the number of events was 316/3111 (173 events per 1000 person-years [E/1000PY], 95% confidence interval [CI]: 154-192 E/1000PY) in the pre-pandemic period, and 326/2746 (245 E/1000PY, 95% CI: 220-274 E/1000PY) in the pandemic period (crude HR: 1.42, 95% CI: 1.22-1.66; adjusted HR: 1.25, 95% CI: 1.07-1.46). The two sensitivity analyses and subgroup analyses consistently supported these findings. CONCLUSIONS: The study revealed an increased colorectal cancer mortality during the pandemic period, suggesting a continuous impact of the COVID-19 pandemic on the known and unknown risk factors for colorectal cancer for several years. Further studies are necessary to mitigate the adverse effects on patient outcomes.

Thermoreversible helical fibers from photoreactive triphenylene-derived liquid crystals in liquid paraffin.

Liquid crystalline triphenylene derivatives, TPC1p-n (n = 6, 12, 14, 16) were prepared using p-alkoxycinnamate as the [2+2] photo-cyclization site. TPC1p-n (n = 12, 14, 16) showed Colr phase and gave crescent-shaped or helical fibers after UV-irradiated in liquid paraffin solutions at 90 and 110 °C in the Colr temperature range. The apparent photoreaction products were shown to be thermally reversible, i.e. they dissolved in liquid paraffin at high temperatures and reappeared on cooling, indicating that they were aggregates of oligomerized TPC1p-n. The reaction mechanism was discussed in terms of the structure of the liquid crystalline phase.

N-methyl-d-aspartate receptors and glycinergic transmission, respectively, mediate muscle relaxation and immobility of pentobarbital in mice.

Pentobarbital-induced anesthesia is believed to be mediated by enhancement of the inhibitory action of γ-aminobutyric acid (GABA)ergic neurons in the central nervous system. However, it is unclear whether all components of anesthesia induced by pentobarbital, such as muscle relaxation, unconsciousness, and immobility in response to noxious stimuli, are mediated only through GABAergic neurons. Thus, we examined whether the indirect GABA and glycine receptor agonists gabaculine and sarcosine, respectively, the neuronal nicotinic acetylcholine receptor antagonist mecamylamine, or the N-methyl-d-aspartate receptor channel blocker MK-801 could enhance pentobarbital-induced components of anesthesia. Muscle relaxation, unconsciousness, and immobility were evaluated by grip strength, the righting reflex, and loss of movement in response to nociceptive tail clamping, respectively, in mice. Pentobarbital reduced grip strength, impaired the righting reflex, and induced immobility in a dose-dependent manner. The change in each behavior induced by pentobarbital was roughly consistent with that in electroencephalographic power. A low dose of gabaculine, which significantly increased endogenous GABA levels in the central nervous system but had no effect on behaviors alone, potentiated muscle relaxation, unconsciousness, and immobility induced by low pentobarbital doses. A low dose of MK-801 augmented only the masked muscle-relaxing effects of pentobarbital among these components. Sarcosine enhanced only pentobarbital-induced immobility. Conversely, mecamylamine had no effect on any behavior. These findings suggest that each component of anesthesia induced by pentobarbital is mediated through GABAergic neurons and that pentobarbital-induced muscle relaxation and immobility may partially be associated with N-methyl-d-aspartate receptor antagonism and glycinergic neuron activation, respectively.

Clinical utility of computed tomography-based evaluation of trunk muscles in primary sclerosing cholangitis.

PURPOSE: Sarcopenia is well recognized as a prognostic factor of chronic liver diseases. However, its impact on the clinical course of primary sclerosing cholangitis (PSC) is unclear. This study aimed to clarify the importance of trunk muscles evaluated by computed tomography (CT) in the pathophysiology of patients with PSC. MATERIALS AND METHODS: 22 PSC patients (12 men, mean age 42.8 years) were enrolled in this study. Patients who died of hepatic failure or had to receive liver transplantation were defined as event group. 44 age- and gender-matched individuals without hepatic disorder were served as controls. At the level of third lumbar vertebrae, the area of psoas muscle and trunk muscle as well as the CT values of multifidus muscle and subcutaneous fat were evaluated. Based on these, skeletal muscle index (SMI), psoas muscle mass index (PMI) and intramuscular adipose tissue content (IMAC) were calculated. Then we analyzed the relationship between these parameters and laboratory data, Fibrosis-4 index, MELD score and Mayo risk score. RESULTS: At baseline evaluation, SMI and PMI were statistically lower in male PSC patients compared with those in controls (P < 0.05). In male PSC, regarding the laboratory data, PMI was associated with total bilirubin, ALT, ALP, and platelet count (P < 0.05). We found close relationship between PMI and MELD score (R2 = 0.42, P = 0.02). PMI also decreased statistically in male Event group than in non-event group (4.85 vs 7.20, P = 0.01). CONCLUSION: Skeletal muscle mass evaluated by CT scan can be suitable for evaluating clinical and prognostic marker in male PSC.

Granulocyte Colony-stimulating Factor-induced Aortitis with Lung Injury, Splenomegaly, and a Rash During Treatment for Recurrent Extraosseous Mucinous Chondrosarcoma.

We herein report a case of aortitis induced by granulocyte colony-stimulating factor (G-CSF) that coincided with lung injury, splenomegaly, and cutaneous manifestations during treatment for recurrent extraosseous mucinous chondrosarcoma. Computed tomography revealed large-vessel vasculitis, splenomegaly, and pulmonary interstitial changes. Treatment with prednisolone was successful. Because sarcoma is a rare disease, this case is valuable for showing clinicians that G-CSF preparations could cause aortitis regardless of the patient's underlying diseases or therapeutic pharmacological backgrounds.

Quantification of the Plasma Concentrations of Perampanel Using High-Performance Liquid Chromatography and Effects of the CYP3A4*1G Polymorphism in Japanese Patients.

Here, we developed a novel high-performance liquid chromatography (HPLC) method for quantification of perampanel in clinical practice and investigated the relationships between the plasma concentrations of perampanel obtained by this HPLC method and the CYP3A4*1G polymorphism. The developed HPLC method was validated based on US Food and Drug Administration. The developed HPLC method could be performed with a plasma volume of only 200 µL and had a limit of quantification (LOQ) of 2.5 ng/mL. The coefficients of variation (CVs) for intra- and inter-day assays were less than 10.4 and 7.2%, respectively, and the accuracy was <2.4% for both assays. A total of 12 patients who received 2 mg perampanel had C0 values ranging from 70.5 to 451 ng/mL, and the CV showed a large variation of 51.4%. No correlations were observed between the dose-adjusted C0 and the CYP3A4*1G polymorphism. This method was superior to previously reported methods in terms of plasma volume and LOQ and was clinically applicable. Perampanel showed high variations in individual plasma concentrations; however, individual differences could not be predicted from analysis of the CYP3A4*1G polymorphism before perampanel administration. Therefore, after beginning perampanel treatment, the dose should be determined based on the observed plasma concentration.