Circadian and sleep phenotypes in a mouse model of Alzheimer's disease characterized by intracellular accumulation of amyloid ß oligomers.

Disturbances in sleep-wake and circadian rhythms may reportedly precede the onset of cognitive symptoms in the early stages of Alzheimer's disease (AD); however, the underlying mechanisms of these AD-induced sleep disturbances remain unelucidated. To specifically evaluate the involvement of amyloid ß (Aß) oligomers in AD-induced sleep disturbances, we examined circadian and sleep phenotypes using an Aß-GFP transgenic (Aß-GFP Tg) mouse characterized by intracellular accumulation of Aß oligomers. The circadian rhythm and free-running period of wheel running activity were identical between Aß-GFP Tg and littermate wild-type mice. The durations of rapid eye movement (REM) sleep were elongated in Aß-GFP Tg mice; however, the durations of non-REM sleep and wakefulness were unaffected. The Aß-GFP Tg mice exhibited shifts in the electroencephalogram (EEG) power spectra toward higher frequencies in the inactive light phase. These findings suggest that the intracellular accumulation of Aß oligomers might be associated with sleep quality; however, its impact on circadian systems is limited.

Supplementation with Ashitaba (Angelica keiskei) Yellow Stem Exudate Prevents Aging-Induced Thrombotic Tendencies and Systemic Inflammation Without Affecting Body Weight Gain in Mice.

Angelica keiskei Koidzumi (Ashitaba) is a traditional folk medicine and health supplement in Japan. Ashitaba yellow stem exudate (AYE) contains abundant chalcones and thus has the potential to treat and prevent many pathological states such as cancer, inflammation, obesity, diabetics, thrombosis, and hypertension. Levels of plasminogen activator inhibitor 1 (PAI-1), a key regulator of the fibrinolytic system, increase with age in mouse plasma. Therefore, we aimed to determine the effects of AYE on plasma thrombotic parameters in aging mice. Long-term (52 weeks) AYE supplementation significantly decreased age-induced increases of PAI-1 in mouse plasma. Supplementation with AYE decreased levels of the acute-phase and fibrinolytic protein plasma plasminogen, and significantly decreased those of tumor necrosis factor α. These results suggested that continuous intake of AYE throughout life decreases age-induced systemic inflammation and prevents thrombotic tendencies without affecting body weight gain in aged mice. Our findings showed that supplementing diets with AYE might help to prevent thrombotic diseases in elderly individuals.

Metabolic profiles of saliva in male mouse models of chronic sleep disorders induced by psychophysiological stress.

Disordered sleep is a global social problem and an established significant risk factor for psychological and metabolic diseases. We profiled non-targeted metabolites in saliva from mouse models of chronic sleep disorder (CSD). We identified 288 and 55 metabolites using CE-FTMS and LC-TOFMS, respectively, among which concentrations of 58 (CE-FTMS) and three (LC-TOFMS) were significantly changed by CSD. Pathway analysis revealed that CSD significantly suppressed glycine, serine and threonine metabolism. Arginine and proline metabolic pathways were among those that were both upregulated and downregulated. Pathways of alanine, aspartate and glutamate metabolism, genetic information processing, and the TCA cycle tended to be downregulated, whereas histidine metabolism tended to be upregulated in mice with CSD. Pyruvate, lactate, malate, succinate and the glycemic amino acids alanine, glycine, methionine, proline, and threonine were significantly decreased, whereas 3-hydroxybutyric and 2-hydroxybutyric acids associated with ketosis were significantly increased, suggesting abnormal glucose metabolism in mice with CSD. Increases in the metabolites histamine and kynurenic acid that are associated with the central nervous system- and decreased glycine, might be associated with sleep dysregulation and impaired cognitive dysfunction in mice with CSD. Our findings suggested that profiling salivary metabolites could be a useful strategy for diagnosing CSD.

A ketogenic diet containing medium-chain triglycerides reduces REM sleep duration without significant influence on mouse circadian phenotypes.

Ketogenic diets (KDs) affect the circadian rhythms of behavior and clock gene expression in experimental animals. However, these diets were designed to simulate a fasting state; thus, whether these effects are caused by diet-induced ketogenesis or persistent starvation is difficult to distinguish. The present study aimed to define the effects of a KD containing medium-chain triglycerides (MCT-KD) that increase blood ketone levels without inducing carbohydrate starvation, on circadian rhythms and sleep regulation. Mice were fed with a normal diet (CTRL) or MCT-KD for 2 weeks. Blood ß-hydroxybutyrate levels were significantly increased up to 2 mM by the MCT-KD, whereas body weight gain and blood glucose levels were identical between the groups, suggesting that ketosis accumulated without carbohydrate starvation in the MCT-KD mice. Circadian rhythms of wheel-running activity and core body temperature were almost identical, although wheel-running was slightly reduced in the MCT-KD mice. The circadian expression of the core clock genes, Per1, Per2, Bmal1, and Dbp in the hypothalamus, heart, liver, epididymal adipose tissues, and skeletal muscle were almost identical between the CTRL and MCT-KD mice, whereas the amplitude of hepatic Per2 and adipose Per1 expression was increased in MCT-KD mice. The MCT-KD reduced the duration of rapid-eye-movement (REM) sleep without affecting the duration of non-REM sleep and the duration of wakefulness. These findings suggested that the impact of ketone bodies on circadian systems are limited, although they might reduce locomotor activity and REM sleep duration.

Tiotropium for refractory cough in asthma via cough reflex sensitivity: A randomized, parallel, open-label trial.

BACKGROUND: We previously reported in an uncontrolled study that tiotropium alleviated chronic cough in asthma refractory to inhaled corticosteroids and long-acting ß2 agonists (ICS/LABA) by modulating capsaicin cough reflex sensitivity (C-CRS). OBJECTIVE: We sought to determine the antitussive effects of tiotropium for refractory cough in asthma in a randomized, parallel, open-label trial. METHODS: A total of 58 patients with asthma having chronic cough refractory to ICS/LABA were randomized in a 2:1 ratio to add tiotropium 5 µg (39 patients) or theophylline 400 mg (19 patients) for 4 weeks. Patients underwent workups, including capsaicin cough challenge test and subjective measures such as cough severity visual analog scales (VAS). We adopted C5, the lowest capsaicin concentration to induce at least 5 coughs, as an index of C-CRS. We also performed a posthoc analysis to identify factors predicting tiotropium responders, who found an improvement of at least 15 mm in cough severity VAS. RESULTS: A total of 52 patients (tiotropium, 38; theophylline, 14) completed the study. Both tiotropium and theophylline significantly improved cough severity VAS and cough-specific quality of life. Tiotropium, but not theophylline, significantly increased C5, whereas pulmonary function did not change in either group. In addition, changes in cough severity VAS correlated with changes in C5 values in the tiotropium group. A posthoc analysis revealed that heightened C-CRS (C5 ≤1.22 µM) before the addition of tiotropium was an independent predictor for tiotropium responders. CONCLUSION: Tiotropium may alleviate chronic cough in asthma refractory to ICS/LABA by modulating C-CRS. Heightened C-CRS may predict responsiveness to tiotropium for refractory cough in asthma. TRIAL REGISTRATION: Clinical Trials Registry ID: UMIN000021064 (https://center6.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno=R000024253).

Periostin activates distinct modules of inflammation and itching downstream of the type 2 inflammation pathway.

Atopic dermatitis (AD) is a chronic relapsing skin disease accompanied by recurrent itching. Although type 2 inflammation is dominant in allergic skin inflammation, it is not fully understood how non-type 2 inflammation co-exists with type 2 inflammation or how type 2 inflammation causes itching. We have recently established the FADS mouse, a mouse model of AD. In FADS mice, either genetic disruption or pharmacological inhibition of periostin, a downstream molecule of type 2 inflammation, inhibits NF-κB activation in keratinocytes, leading to downregulating eczema, epidermal hyperplasia, and infiltration of neutrophils, without regulating the enhanced type 2 inflammation. Moreover, inhibition of periostin blocks spontaneous firing of superficial dorsal horn neurons followed by a decrease in scratching behaviors due to itching. Taken together, periostin links NF-κB-mediated inflammation with type 2 inflammation and promotes itching in allergic skin inflammation, suggesting that periostin is a promising therapeutic target for AD.

Spontaneous regression of lymphovascular invasion and metastasis of malignant melanoma: ultrasound findings.

This report presents a case of malignant melanoma in a 40-year-old male who underwent resection of the tumor in his right ankle. Eleven months after the resection, a subcutaneous mass was observed on his right femur. Ultrasound examination revealed a hypoechoic tubular structure in the right thigh, with a small amount of blood flow in the lesion. Using ultrasound and fine-needle aspiration, the patient was diagnosed with metastasis and lymphovascular invasion of malignant melanoma. Treatment with an immune checkpoint inhibitor was originally scheduled, but the lesion disappeared spontaneously after the fine-needle aspiration.

Identification of salivary microRNA profiles in male mouse model of chronic sleep disorder.

Chronic sleep disorders (CSD) comprise a potential risk factor for metabolic and cardiovascular diseases, obesity and stroke. Thus, the identification of biomarkers for CSD is an important step in the early prevention of metabolic dysfunctions induced by sleep dysfunction. Diagnostic saliva samples can be easily and noninvasively collected. Thus, we aimed to identify whole microRNA (miRNA) profiles of saliva in control and psychophysiologically stressed CSD mouse models and compare them at Zeitgeber time (ZT) 0 (lights on) and ZT12 (lights off). The findings of two-way ANOVA revealed that the expression of 342 and 109 salivary miRNAs was affected by CSD and the time of day, respectively. Interactions were found in 122 miRNAs among which, we identified 197 (ZT0) and 62 (ZT12) upregulated, and 40 (ZT0) and seven (ZT12) downregulated miRNAs in CSD mice. We showed that miR-30c-5p, which is elevated in the plasma of patients with hypersomnia, was upregulated in the saliva of CSD mice collected at ZT0. The miRNAs, miR-10a-5p, miR-146b-5p, miR-150-5p, and miR-25-3p are upregulated in the serum of humans with poor sleep quality, and these were also upregulated in the saliva of CSD mice collected at ZT0. The miRNAs miR-30c, miR146b-5p, miR150, and miR-25-5p are associated with cardiovascular diseases, and we found that plasma concentrations of brain natriuretic peptides were significantly increased in CSD mice. The present findings showed that salivary miRNA profiles could serve as useful biomarkers for predicting CSD.

An autopsy case of immune-related severe colitis due to long-term use of nivolumab in a patient with non-small cell lung cancer.

Immune checkpoint inhibitors (ICIs) have been developed as cornerstones of cancer therapy, but the growing use of ICIs has induced immune-related adverse effects (irAEs). Immune-related colitis, which is one of the most common irAEs, generally occurs 2-4 months after ICI treatment initiation and can be life threatening. Therefore, early diagnosis and appropriate management are required. A rare autopsy case of nivolumab-related severe colitis that occurred 34 months after the start of treatment and recurred despite temporal remission with corticosteroids and infliximab is presented. Physicians should be aware of the possibility of late-onset irAEs in patients on receiving long-term ICI treatment.

Assessment of the risk of disease transmission during fine-needle aspiration cytology under ultrasound guidance by visualization of droplet and aerosol formation.

PURPOSE: Fine-needle aspiration cytology (FNAC) under ultrasound guidance is clinically useful, but there is a risk of spreading infection by generating droplets of contaminated fluids during the procedure. Risk assessment to better control infection remains to be established. The aim of this study was to estimate infection risks during FNAC by visualization of droplet production and deposition using a simulation model. METHODS: The simulation comprised a puncture needle, a device for holding the needle, and a fluid specimen containing fluorescent particles as a model. Simulating each step of FNAC (removal of the inner and outer cylinder and transferring the specimen onto a glass slide), the generation and deposition of droplets were visualized using a laser. RESULTS: After removal of the inner cylinder, an aerosol of droplets in the air surrounding the needle was observed. After removal of the outer cylinder, several large droplets precipitating onto the circumjacent surface were observed. From the beginning of transferring the specimen, a large amount of sizeable droplets first moving away and then precipitating was observed, followed by the production of a cluster of fine droplets drifting and spreading through the air. CONCLUSIONS: Here, the generation of droplets at each step of FNAC, precipitation of large droplets onto the circumjacent surface, and drifting and spreading through the air of fine droplets was visualized. These results emphasize the need for precautions to prevent the transmission of infectious agents during FNAC.

Genetic variations in the ATP-binding cassette transporter ABCC10 are associated with neutropenia in Japanese patients with lung cancer treated with nanoparticle albumin-bound paclitaxel.

ABCC10/MRP7, an ATP-binding cassette (ABC) transporter, has been implicated in the extracellular transport of taxanes. Our group reported that the ABCC10 single nucleotide polymorphism (SNPs), rs2125739, influences docetaxel cytotoxicity in lung cancer cell lines as well as its side effects in clinical practice. In this study, we investigated whether the rs2125739 variant could affect paclitaxel (PTX) cytotoxicity in lung cancer cell lines. We also investigated the effect of rs2125739 on the efficacy and safety of nanoparticle albumin-bound PTX (nab-PTX) in clinical practice. The association between rs2125739 genotypes and the 50% inhibitory concentration (IC50) of PTX was investigated in 18 non-small cell lung cancer (NSCLC) cell lines, HeLa cells, and genome-edited HeLa cells. Next, blood samples from 77 patients with NSCLC treated with carboplatin plus nab-PTX were collected and analyzed for six SNPs, including rs2125739. The clinical outcomes among the different genotype groups were evaluated. In NSCLC cell lines, HeLa cells, and genome-edited HeLa cells, the IC50 was significantly higher in the ABCC10 rs2125739 T/T group than in the T/C and C/C groups. In 77 patients with NSCLC, there were no significant differences in clinical outcomes between the T/T and T/C groups. However, the rs2125739 T/T genotype was associated with a higher frequency of Grades 3/4 neutropenia. In contrast, there was no association between other SNPs and clinical efficacy or neutropenia. Our results indicate that the ABCC10 rs2125739 variant is associated with neutropenia in response to nab-PTX treatment.

High-Pressure Synthesis of Superconducting Sn3S4 Using a Diamond Anvil Cell with a Boron-Doped Diamond Heater.

High-pressure techniques open exploration of functional materials in broad research fields. An established diamond anvil cell with a boron-doped diamond heater and transport measurement terminals has performed the high-pressure synthesis of a cubic Sn3S4 superconductor. X-ray diffraction and Raman spectroscopy reveal that the Sn3S4 phase is stable in the pressure range of P > 5 GPa in a decompression process. Transport measurement terminals in the diamond anvil cell detect a metallic nature and superconductivity in the synthesized Sn3S4 with a maximum onset transition temperature (Tconset) of 13.3 K at 5.6 GPa. The observed pressure-Tc relationship is consistent with that from the first-principles calculation. The observation of superconductivity in Sn3S4 opens further materials exploration under high-temperature and -pressure conditions.

Pretreatment Alveolar Nitric Oxide Levels Predict Improvement of Pulmonary Function 1 Year Following Anti-Asthma Treatments in Patients with Inhaled Corticosteroid-Naïve Asthma.

INTRODUCTION: Inhaled corticosteroids (ICS) are fundamental agents to subside airway inflammation and improve forced expiratory volume in 1 s (FEV1) among asthmatics. Alveolar concentrations of nitric oxide (CANO), as well as the classical fraction of exhaled nitric oxide (FeNO50), are associated with the pathophysiology of asthma. However, the association between pretreatment CANO levels and response to anti-asthma treatments, including ICS, remains unknown. METHODS: We retrospectively analyzed 107 patients newly diagnosed with asthma. ICS in combination with long-acting ß2-agonists (ICS/LABA) was initiated. FEV1 and FeNO levels were evaluated at diagnosis and were followed up at 6 and 12 months after the treatment intervention. CANO levels were estimated using various expiratory flows of FeNO measurements. Factors associated with annual changes in FEV1 (ΔFEV1) were analyzed. Patients with a ΔFEV1 <-20 mL were defined as "poor-responders." RESULTS: FEV1, FeNO50, and CANO levels significantly improved by anti-asthma treatments. The average ΔFEV1 was 85 (176) mL. Eighty-two patients continuously took ICS/LABA treatment. Higher pretreatment CANO levels and continuous use of LABA were independent predictive factors for the improvement of FEV1 on multivariate analysis. The decline in FeNO50 and CANO levels by the anti-asthma treatments was significantly greater in 81 responders than in 26 poor-responders. CANO, but not FeNO50, levels at 12 months were significantly higher in poor-responders than in responders (p = 0.009). CONCLUSION: Levels of CANO, but not FeNO50, predict changes in pulmonary function in ICS-naïve asthmatics. Meanwhile, persistently high levels of CANO may be related to poor responsiveness to treatments assessed by ΔFEV1.

Crystal Growth and High-Pressure Effects of Bi-Based Superconducting Whiskers.

Three growth methods were tested for producing high-transition temperature superconducting Bi2Sr2Ca n-1Cu n O2n+4+δ whiskers, employing different ways to focus a compressive stress and size effect of the precursors. First, thermographic imaging was used to investigate thermal stress from temperature distribution in the precursors during growth annealing. To enhance thermal stress in the precursors, a thermal cycling method and a Ag-paste coating method were proposed and found to significantly accelerate the whisker growth. The use of pulverized precursors also promoted whisker growth, possibly due to contribution from the vapor-liquid-solid growth mechanism. The obtained whiskers revealed the typical composition, diffraction patterns, and superconducting properties of the Bi-2212 phase. The proposed methods were able to stably produce longer whiskers compared to the conventional method. Using the obtained whiskers, electrical transport measurements under high pressure were successfully performed up to around 50 GPa.

Usefulness of lactate dehydrogenase in differentiating abnormal cervical lymphadenopathy.

BACKGROUND: Cervical lymphadenopathy is commonly seen in general practice, and its etiology is diverse. Establishing the diagnostic strategy for lymphadenopathy would be desirable to avoid overlooking neoplasms or other critical conditions. This study aims to identify the useful laboratory parameters for cervical lymphadenopathy that require clinical observation or intervention. METHODS: The participants were outpatients presenting cervical swelling or cervical lymph node (LN) pain who consulted the General Internal Medicine department from 2010 to 2016. We evaluated the characteristics, physical findings, and laboratory parameters with final diagnoses by multivariate logistic regression analysis. We categorized the final diagnoses as "Clinical Intervention Required Group (CIRG)" including necrotizing lymphadenitis, hematologic neoplasms, metastatic lymphadenopathy, tuberculous lymphadenitis, bacterial infectious diseases, infectious mononucleosis, autoimmune diseases, and other abnormal conditions or "No-CIRG" not requiring further clinical observation or intervention. RESULTS: We evaluated 409 participants, with 130 (31.8%) diagnosed as belonging to the CIRG. There was an association between CIRG and various parameters: age ≥60 years old (adjusted odds ratio [AOR], 2.70; 95% confidence interval [CI], 1.48-4.90), having a referral (AOR, 1.83; 95% CI, 1.12-3.00), diameter of LN ≥ 2 cm (AOR, 1.91; 95% CI, 1.05-3.48), fixed LNs (AOR, 2.74; 95% CI, 1.02-7.37), and lactate dehydrogenase (LD) ≥400 U/L (AOR, 3.78; 95% CI, 1.46-9.77). Eighty-two percent of LD ≥ 400 cases in the CIRG were infectious mononucleosis or necrotizing lymphadenitis. CONCLUSIONS: Besides the clinical indicators reported previously, we may apply an elevated LD level as a useful indicator of cervical lymphadenopathy that requires further clinical observation or intervention.

Effectiveness of trauma-focused cognitive behavioral therapy for Japanese children and adolescents in community settings: a multisite randomized controlled trial.

BACKGROUND: Trauma-focused cognitive behavioural therapy (TF-CBT) is an efficacious treatment model for children and adolescents with trauma-related disorders. However, few studies have been conducted in community settings, and there have been no randomized controlled trials in Asian countries. OBJECTIVE: To evaluate the effectiveness of TF-CBT in regular community settings in Japan through comparison with a waitlist with minimal services control condition. METHOD: Thirty Japanese children and adolescents with posttraumatic stress disorder symptoms (22 females, eight males, mean age = 13.90, range = 6-18) were randomly assigned to 12 sessions of TF-CBT or the waitlist control condition. The primary outcome measure was the Kiddie Schedule for Affective Disorders and Schizophrenia score assessed by blinded evaluators one month later. RESULTS: The mean number of sessions was 12 (range: 11-13) in the TF-CBT group and 4.87 (range: 3-7) in the control group. Intention to treat analysis showed that the TF-CBT group achieved significantly greater symptom reduction than did the control group. The effect size (Cohen's d) between the TF-CBT and control groups was 0.96 (p =.014) for posttraumatic symptoms and 1.15 (p =.004) for depressive symptoms. However, the TF-CBT group did not show better results than the control group with regard to improvements in anxiety symptoms, psychosocial functioning, and behavioural problems. CONCLUSIONS: The findings provided preliminary evidence of the effectiveness of TF-CBT for treating youth with trauma in community mental health facilities. TF-CBT in the Japanese context proved identical to the original, demonstrating that it is also suitable for use with children and adolescents in non-Western settings.

Antecedentes: La Terapia Cognitivo Conductual Centrada en el Trauma (TF-CBT en su sigla en inglés) es un modelo de tratamiento eficaz para niños y adolescentes con trastornos relacionados con el trauma. Sin embargo, hasta la fecha solo se han realizado unos pocos estudios en entornos comunitarios y no se han realizado ensayos controlados aleatorios en países asiáticos.Objetivo: Este estudio buscó evaluar la efectividad de la TF-CBT en entornos comunitarios regulares en Japón, en comparación con el tratamiento habitual (TAU en su sigla en inglés).Métodos: Treinta niños y adolescentes japoneses (22 mujeres, 8 hombres, promedio de edad = 13.90, rango = 6-18) fueron asignados aleatoriamente a 12 sesiones de la TF-CBT o al grupo TAU. La medida de resultado primaria fue el puntaje K-SADS (Calendario Kiddie para Trastornos Afectivos y Esquizofrenia) evaluado por evaluadores cegados un mes después del tratamiento.Resultados: El análisis de 'intención de tratar' mostró que el grupo TF-CBT logró una reducción significativa de síntomas, mayor que el grupo control. El tamaño del efecto (d de Cohen) entre el grupo TF-CBT y el grupo TAU fue de 0.96 (p =.014) para los síntomas postraumáticos y 1.15 (p =.004) para los síntomas depresivos.Conclusión: Los hallazgos revelaron que la TF-CBT es eficaz para tratar a jóvenes traumatizados en centros comunitarios de salud mental y podría implementarse con éxito en Japón.

Value of TTF-1 expression in non-squamous non-small-cell lung cancer for assessing docetaxel monotherapy after chemotherapy failure.

Docetaxel is one of the standard second/third-line treatments for non-small-cell lung cancer (NSCLC) following a failed response to prior cytotoxic chemotherapy. The predictive biomarker for the effectiveness of docetaxel therapy remains undetermined. However, thyroid transcription factor-1 (TTF-1) is known to be a good prognostic factor for a variety of chemotherapies. To investigate the association between TTF-1 expression and docetaxel monotherapy outcome, 82 patients with non-squamous NSCLC who received second/third-line docetaxel monotherapy were retrospectively screened. All backgrounds were well-balanced whether or not tumor TTF-1 was expressed, and the present clinical outcomes were similar to those reported by previous clinical studies. A better clinical outcome was indicated in TTF-1 positive compared with TTF-1 negative patients, with disease control rates of 69% vs. 42%, respectively (P=0.03) and median overall survival of 393 days vs. 221.5 days, respectively (P<0.01). Furthermore, progression free survival tended to be longer in TTF-1 positive compared with TTF-1 negative patients (median, 100 days vs. 67 days; P=0.09). Multivariate analysis revealed that TTF-1 positivity was a unique significant predictor for assessing overall survival after docetaxel monotherapy. TTF-1 positivity may be useful for predicting survival outcome in patients who received docetaxel monotherapy after failure of prior chemotherapy.