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What is the central question of this study? Increased work of breathing and the accumulation of metabolites have neural and cardiovascular consequences through a respiratory muscle-induced metaboreflex. The influence of the respiratory muscle-induced metaboreflex on splanchnic blood flow in humans remains unknown. What is the main finding and its importance? Coeliac artery blood flow decreased gradually during inspiratory resistive breathing, accompanied by a progressive increase in arterial blood pressure. It is possible that the respiratory muscle-induced metaboreflex contributes to splanchnic blood flow regulation.The purpose of this study was to clarify the effect of increasing inspiratory muscle work on coeliac artery blood flow. Eleven healthy young males completed the study. The subjects performed voluntary hyperventilation with or without inspiratory resistance (loading or non-loading trial; tidal volume of 40% of vital capacity and breathing frequency of 20 breaths/min). The loading trial was conducted with inspiratory resistance (40% of maximal inspiratory pressure) and was terminated when the subjects could no longer maintain the target tidal volume or breathing frequency. The non-loading trial was conducted without inspiratory resistance and was of the same duration as the loading trial. Arterial blood pressure was recorded using finger photoplethysmography, and coeliac artery blood flow was measured using Doppler ultrasound. Mean arterial blood pressure increased gradually during the loading trial (mean ± SD; from 89.0 ± 10.8 to 103.9 ± 17.3 mmHg) but not in the non-loading trial (from 88.7 ± 5.9 to 90.4 ± 9.9 mmHg). Coeliac artery blood flow and coeliac vascular conductance decreased gradually during the loading trial (from 601.2 ± 155.7 to 482.6 ± 149.5 mL/min and from 6.9 ± 2.2 to 4.8 ± 1.7 mL/min/mmHg, respectively) but were unchanged in the non-loading trial (from 630.7 ± 157.1 to 635.6 ± 195.7 mL/min and from 7.1 ± 1.8 to 7.2 ± 2.9 mL/min/mmHg, respectively). These results show that increasing inspiratory muscle work affects splanchnic blood flow regulation, and we suggest that this might be mediated by the inspiratory muscle-induced metaboreflex.

Background/Aim: Sarcopenia increases the mortality in patients with cirrhosis. Approximately 60% of zinc is accumulated in skeletal muscle. We aimed to determine the role of subclinical zinc deficiency on sarcopenia development in patients with cirrhosis. Patients and Methods: We enrolled 151 patients with cirrhosis and divided them into the group with normal serum zinc levels (Group N: 80-130 μg/dl; n=38) and group with subclinical zinc deficiency (Group D

Objective To explore the trends in patient characteristics and implant survivorship (IS) for primary total knee arthroplasty (TKA) over the past three decades. Methods This retrospective study enrolled a total of 635 knees who underwent TKA from 1985 to 2014. They were divided into three groups: group A, 125 knees in 1985–1994; group B, 203 knees in 1995–2004; and group C, 307 knees A in 2005–2014. The patient characteristics and IS were compared. Results The mean age of patients undergoing TKA was getting older: 65.3 ± 9.7, 69.1 ± 10.0, and 74.6 ± 8.4 years, in groups A, B, and C, respectively (p = .001). The proportion of patients Conclusions From these trends, we can estimate that the number of patients undergoing TKA will further increase in the future in an aging society.

Respiratory modulation of sympathetic vasomotor outflow to skeletal muscles (muscle sympathetic nerve activity; MSNA) occurs in resting humans. Specifically, MSNA is highest at end-expiration and lowest at end-inspiration during quiet, resting breathing. We tested the hypothesis that within-breath modulation of MSNA would be amplified during graded leg cycling. Thirteen (n = 3 females) healthy young (age: 25.2 ± 4.7 yr) individuals completed all testing. MSNA (right median nerve) was measured at rest (baseline) and during semirecumbent cycle exercise at 40%, 60%, and 80% of maximal workload (Wmax). MSNA burst frequency (BF) was 20.0 ± 4.0 bursts/min at baseline and was not different during exercise at 40%Wmax (21.3 ± 3.7 bursts/min; P = 0.292). Thereafter, MSNA BF increased significantly compared with baseline (60%Wmax: 31.6 ± 5.8 bursts/min; P < 0.001, 80%Wmax: 44.7 ± 5.3 bursts/min; P < 0.001). At baseline and all exercise intensities, MSNA BF was lowest at end-inspiration and greatest at mid-to-end expiration. The within-breath change in MSNA BF (ΔMSNA BF; end-expiration minus end-inspiration) gradually increased from baseline to 60%Wmax leg cycling, but no further increase appeared at 80%Wmax exercise. Our results indicate that within-breath modulation of MSNA is amplified from baseline to moderate intensity during dynamic exercise in young healthy individuals, and that no further potentiation occurs at higher exercise intensities. Our findings provide an important extension of our understanding of respiratory influences on sympathetic vasomotor control., Published online 13 August 2021

Koji Ishida,1 Keita Nagira,1 Hiroshi Hagino,2 Makoto Enokida,1 Ikuta Hayashi,1 Masako Hayashibara,1 Chikako Takeda,1 Hideki Nagashima1 1Department of Orhopedic Surgery, Faculty of Medicine, Tottori University, Yonago, Tottori, Japan; 2School of Health Science, Faculty of Medicine, Tottori University, Yonago, Tottori, JapanCorrespondence: Keita NagiraDepartment of Orhopedic Surgery, Faculty of Medicine, Tottori University, 36-1 Nishi-cho, Yonago, Tottori, JapanTel +81-859-38-6587Fax +81-859-38-6589Email nagira@tottori-u.ac.jpPurpose: To investigate the incidence and clinical characteristics of rheumatoid arthritis (RA) presenting with shoulder monoarthritis.Patients and Methods: Our study included 113 patients (77 females; mean age, 63.0 ± 13.1 years) whom we newly diagnosed with RA in 2012– 2016. We investigated cases with onset from shoulder monoarthritis. Specifically, we examined physical findings, blood test results, radiographic findings, magnetic resonance imaging (MRI) findings, and duration from initial visit to diagnosis. RA was diagnosed based on the 2010 American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) classification criteria.Results: Overall, mean 2010 ACR/EULAR criteria score was 6.8 ± 1.8, and median duration to diagnosis was 3 days (interquartile range: 0– 14). Two patients (1.8%) were identified as having RA with onset from shoulder monoarthritis. Both were late middle-aged women with MRI findings of rotator cuff tear and remarkable synovial proliferation. However, neither patient fulfilled the 2010 ACR/EULAR criteria. It took 85 and 98 days to make a definitive diagnosis, respectively.Conclusion: Early diagnosis is difficult when RA synovitis develops from shoulder monoarthritis, especially, in elderly patients who have a rotator cuff tear. In addition to MRI, culture-based and pathological examinations may be helpful for early diagnosis of RA.Keywords: rheumatoid arthritis, monoarthritis, shoulder, rotator cuff tear

It is unclear whether blood flow restriction (BFR) accelerates the adaptation of the time constant (τ) of phase II oxygen uptake (VO2) kinetics in the moderate-intensity exercise domain via moderate-intensity aerobic training. Therefore, healthy participants underwent moderate-intensity [45–60% VO2 Reserve] aerobic cycle training with or without BFR (BFR group, n = 9; CON group, n = 9) for 8 weeks to evaluate VO2 kinetics during moderate-intensity cycle exercise before (Pre) and after 4 (Mid) and 8 (Post) weeks of training. Both groups trained for 30 min, 3 days weekly. BFR was performed for 5 min every 10 min by applying cuffs to the upper thighs. The τ significantly decreased by Mid in the BFR group (23.7 ± 2.9 s [Pre], 15.3 ± 1.8 s [Mid], 15.5 ± 1.4 s [Post], P < 0.01) and by Post in the CON group (27.5 ± 2.0 s [Pre], 22.1 ± 0.7 s [Mid], 18.5 ± 1.9 s [Post], P < 0.01). Notably, the BFR group’s τ was significantly lower than that of the CON group at Mid (P < 0.01) but not at Post. In conclusion, BFR accelerates the adaptation of VO2 kinetics at the onset of exercise by moderate-intensity aerobic training.

It is unclear whether blood flow restriction (BFR) accelerates the adaptation of the time constant (τ) of phase II oxygen uptake ([Formula: see text]) kinetics in the moderate-intensity exercise domain via moderate-intensity aerobic training. Therefore, healthy participants underwent moderate-intensity [45-60% [Formula: see text] Reserve] aerobic cycle training with or without BFR (BFR group, n = 9; CON group, n = 9) for 8 weeks to evaluate [Formula: see text] kinetics during moderate-intensity cycle exercise before (Pre) and after 4 (Mid) and 8 (Post) weeks of training. Both groups trained for 30 min, 3 days weekly. BFR was performed for 5 min every 10 min by applying cuffs to the upper thighs. The τ significantly decreased by Mid in the BFR group (23.7 ± 2.9 s [Pre], 15.3 ± 1.8 s [Mid], 15.5 ± 1.4 s [Post], P 0.01) and by Post in the CON group (27.5 ± 2.0 s [Pre], 22.1 ± 0.7 s [Mid], 18.5 ± 1.9 s [Post], P 0.01). Notably, the BFR group's τ was significantly lower than that of the CON group at Mid (P 0.01) but not at Post. In conclusion, BFR accelerates the adaptation of the [Formula: see text] kinetics of phase II by moderate-intensity aerobic training.

Molecular targeted agents are pharmacologically used to treat liver fibrosis and have gained increased attention. The present study examined the preventive effect of lenvatinib on experimental liver fibrosis and sinusoidal capillarization as well as the in vitro phenotypes of hepatic stellate cells. LX‐2, a human stellate cell line, was used for in vitro studies. In vivo liver fibrosis was induced in F344 rats using carbon tetrachloride by intraperitoneal injection for 8 weeks, and oral administration of lenvatinib was started two weeks after initial injection of carbon tetrachloride. Lenvatinib restrained proliferation and promoted apoptosis of LX‐2 with suppressed phosphorylation of extracellular signal‐regulated kinase 1/2 and AKT. It also down‐regulated COL1A1, ACTA2 and TGFB1 expressions by inhibiting the transforming growth factor‐β1/Smad2/3 pathway. Treatment with lenvatinib also suppressed platelet‐derived growth factor‐BB‐stimulated proliferation, chemotaxis and vascular endothelial growth factor‐A production, as well as basic fibroblast growth factor‐induced LX‐2 proliferation. In vivo study showed that lenvatinib attenuated liver fibrosis development with reduction in activated hepatic stellate cells and mRNA expression of profibrogenic markers. Intrahepatic neovascularization was ameliorated with reduced hepatic expressions of Vegf1, Vegf2 and Vegfa in lenvatinib‐treated rats. Collectively, these results suggest the potential use of lenvatinib as a novel therapeutic strategy for liver fibrosis.

Some researchers are concerned that exercise training with the blood flow restriction (BFR) technique induces an exaggeration in blood pressure response and potentiates adverse cardiovascular events. In the present study, we demonstrate that the blood pressure response to arm-curl exercise was intensified by the BFR technique, and the degree of intensification was associated with a blood pressure response to postexercise muscle ischemia of the elbow flexors, which elicit a muscle metaboreflex. Novelty: BFR technique intensifies blood pressure response to exercise, which was associated with a blood pressure response in postexercise muscle ischemia-induced muscle metaboreflex.

BACKGROUND Prediction of HAIC treatment response is important for improving the prognosis in patients with hepatocellular carcinoma (HCC). The progression of HCC is related to hypercoagulability and angiogenesis. It is known that ADAMTS13 and von Willebrand factor (VWF) are related to hypercoagulability. In addition, previous study reported that the association between ADAMTS13 and VWF, and angiogenesis via vascular endothelial growth factor (VEGF). Recently, ADAMTS13 and VWF have been associated with the prognosis in patients with various kinds of cancer undergoing chemotherapy. AIM To investigate whether ADAMTS13 and VWF become useful biomarkers of treatment response in HCC patients before the initiation of HAIC treatment. METHODS Seventy-two patients were enrolled in this study. ADAMTS13 activity (ADAMTS13:AC), VWF antigen (VWF:Ag) and VEGF levels were determined via enzyme-linked immunosorbent assay. Univariable and multivariable analyses were performed to determine the predictive factors of treatment response in patients with HCC undergoing HAIC treatment. RESULTS ADAMTS13:AC levels in HCC patients with stable disease (SD) + partial response (PR) of HAIC treatment were significantly higher than those with progressive disease (PD) (P < 0.05). In contrast, VWF:Ag/ADAMTS13:AC ratio and VEGF levels in HCC patients with SD + PR were significantly lower than those with PD (both P < 0.05). Patients with high VWF:Ag/ADAMTS13:AC ratio (> 2.7) had higher VEGF levels than those with low ratio (≤ 2.7). Multivariable analysis revealed that VWF:Ag/ADAMTS13:AC ratio was a predictive factor of HAIC treatment response. CONCLUSION VWF:Ag/ADAMTS13:AC ratio may become a useful biomarker of treatment response in HCC patients before the initiation of HAIC treatment.

Background and Aim Hypothyroidism might play a crucial role in the pathogenesis of non‐alcoholic fatty liver disease (NAFLD). The association of subclinical hypothyroidism with NAFLD has been inconsistent. The relationship of NAFLD with thyroid function parameters and subclinical hypothyroidism was determined. Methods This cross‐sectional study included 70 patients with subclinical hypothyroidism and 70 controls with euthyroidism matched according to gender, age, and body mass index (BMI). NAFLD was diagnosed via abdominal ultrasonography. The association between NAFLD and subclinical hypothyroidism was analyzed. Results The prevalence of NAFLD was significantly higher in patients with subclinical hypothyroidism than in those with euthyroidism. Multivariate analysis showed that subclinical hypothyroidism was an independent risk factor of NAFLD adjusted by metabolic‐related factors, such as BMI, triglyceride, high‐density lipoprotein‐cholesterol, hypertension, and diabetes. Thyroid‐stimulating hormone (TSH) was an independent risk factor of NAFLD adjusted by the same metabolic‐related factors, but free thyroxine (FT4) was not a risk factor. The FIB‐4 index, a noninvasive marker of liver fibrosis was significantly higher in patients with subclinical hypothyroidism than in those with euthyroidism. Compared with patients with euthyroidism, the proportion of the FIB‐4 index ≥2.67 was significantly higher, and the proportion of the FIB‐4 index, Thyroid‐stimulating hormone elevation, even within the euthyroid range, is an independent risk factor of non‐alcoholic fatty liver disease and may have an influence on the progression of liver fibrosis, even with a normal free T4 level.

What is the central question of this study? Sympathetic vasomotor outflow is reduced during low-intensity dynamic leg exercise in younger individuals: does ageing influence the sympathoinhibitory effect during low-intensity leg cycling? What is the main finding and its importance? Muscle sympathetic nerve activity during low-intensity cycling decreased in older males, as seen in young males. It is possible that cardiopulmonary baroreflex-mediated inhibition of sympathetic vasomotor outflow during dynamic leg exercise is preserved in healthy older males.Muscle sympathetic nerve activity (MSNA) is reduced during low-intensity dynamic leg exercise in young males. It is suggested that this inhibition is mediated by loading of the cardiopulmonary baroreceptors. The purpose of this study was to clarify the impact of age on MSNA during dynamic leg exercise. Nine younger males (YM, mean ± SD, 20 ± 1 years) and nine older males (OM, 72 ± 3 years) completed the study. The subjects performed two 4-min cycling exercises at 10% of their heart rate reserve using a cycle ergometer in a semirecumbent position (MSNA and estimated central venous pressure (eCVP) trials). MSNA was recorded via microneurography of the left radial nerve. The CVP was estimated based on peripheral venous pressure, which was monitored using a cannula in the right large antecubital vein. The magnitude of the increase in mean arterial blood pressure during leg cycling was larger in OM (+9.3 ± 5.5 mmHg) compared with YM (+2.8 ± 4.7 mmHg). MSNA burst frequency was decreased during cycling in both YM (-8.1 ± 3.8 bursts/min) and OM (-10.6 ± 3.3 bursts/min), but no significant difference was found between the two groups. The eCVP increased during exercise in both groups, and there was no difference in the changes in eCVP between YM (+1.1 ± 0.4 mmHg) and OM (+1.2 ± 0.7 mmHg). These data indicate that inhibition of sympathetic vasomotor outflow during low-intensity cycling appears in OM as seen in YM. It is possible that the muscle pump-induced loading of the cardiopulmonary baroreflex is preserved during cycling in healthy older males.

After pyroclastic materials are deposited in a watershed following a volcanic eruption, the risk of debris flow initiation may increase during subsequent rainfall events. Clarifying the rainfall-runoff process on tephra-covered slopes is essential to understand the mechanism of debris flow initiation after an eruption. Because the quality and quantity of pyroclastic materials vary from volcano to volcano, and from eruption to eruption of the same volcano, each rainfall-runoff process is expected to differ accordingly. Laboratory rainfall simulation is useful to highlight parameters (rainfall and sample conditions) that may affect the surface runoff process on slopes during and after a volcanic eruption. In this study, a laboratory experiment was conducted using a calibrated rainfall simulator to investigate how the occurrence of surface runoff during the first rainfall after an eruption depends on the fine particle content. Pyroclastic material was volcanic ash collected on Mount Sakurajima, Japan and the fine particle content Fc was adjusted using artificial silt: Sample A (Fc = 20%, control) and Sample B (Fc = 30%, adjusted). The experimental plots (1723.4 cm2 of the projection area) were prepared by filling each sample with a 5 cm thickness at a constant pressure on highly permeable silica sand, and placed at an inclination of 10°. The initial moisture condition of both samples was assumed to be dry (≈ 5% of water content ratio). The rainfall simulation was performed for 3 hours on each sample at an intensity of 30 mm h-1. Runoff water including sediment from the experimental plot during the simulation was captured at the lower end of the plot and the weight was recorded. Two soil moisture sensors were buried 2.5 cm below the surface of each sample to measure the change in volumetric water content (VWC) over time. Runoff water including sediment occurred and increased with time on Sample B though hardly occurred on Sample A. In both samples, the VWC increased with time and eventually approached a constant value. However, the maximum value of the VWC, and the time to reach the maximum value, were different; lower and slower in Sample B. The saturated hydraulic conductivity of Sample B was one order of magnitude lower than that of Sample A. These comparative results suggested that surface runoff may be greater during the first rainfall after an eruption because the infiltration is lower when the fine particle content, that is particle size distribution, in pyroclastic materials is high.

Understanding the dynamic of instream large wood (LW) is essential for reducing hydrogeomorphic hazards in populated mountainous catchments. Quantifying the spatiotemporal distribution of LW is generally the most demanding process for investigating LW dynamics in rivers. Over the last two decades, multiple airborne sensors have been applied for mapping LW in relatively large alluvial rivers. However, those existing approaches are not necessarily suitable for remotely sensing LW in forested headwater streams, mainly due to canopy obstruction, weak illumination, and operational difficulty. Therefore, we tested the applicability of a 5-kilogram commercial backpack mobile laser scanning system for detecting and quantifying LW in a forested headwater stream of southwest Japan. Extremely dense point clouds (~15000 pts/m2) were continuously scanned within 150-meter reach of the 2nd-order stream (slope: 0.045) by a 6-minute walk following rainfall-triggered debris flows. Dimension and volume of LW measured from point clouds were compared to associated field and UAV photogrammetry-based mapping data. Based on a surface shape detection algorithm and subsequent manual filtering of falsely detected objects (e.g., riparian trees), 25 cylinders corresponding to 34.9 m3 total volume were delineated from point clouds. While the UAV photogrammetry-based approach was able to quantify only 2.4% of total LW volume, 75.1% of LW volume was successfully reconstructed by backpack mobile laser scanning. The visibility of the UAV photogrammetry-based approach was substantially limited by the dense riparian vegetation of our study reach. However, underestimation of wood piece length and overestimation of wood piece diameter consistently occurred for both remote sensing approaches. Therefore, further efforts would be made to evaluate the sensitivity of individual parameters used in point cloud processing for LW detection and quantification. Considering the mobility of sensors and data availability of near-surface objects, our case study indicates that backpack mobile laser scanning potentially provides a powerful alternative for more continuous, efficient, and frequent LW mapping, particularly in forested headwater streams.

Mortality and recurrence rates of hepatocellular carcinoma (HCC) are high. Recent studies show that for patients with HCC beyond up-to-seven criteria, treatment with molecular-targeted agents (MTAs) is recommended because the treatment efficiency of transcatheter arterial chemoembolization (TACE) is poor, further, TACE increases decline in liver function. However, the relationship between TACE and liver function decline in patients with HCC within up-to-seven criteria has not been clarified. Hence, we aimed to investigate this relationship. This retrospective observational study included 189 HCC tumors within up-to-seven criteria in 114 Child–Pugh class A patients. Twenty-four (12.7%) tumors were changed from Child–Pugh class A to B after TACE, and 116 (61.4%) tumors exhibited recurrence within 6 months after TACE. Prothrombin time (PT) and albumin–bilirubin (ALBI) score before TACE were significantly associated with liver dysfunction from Child–Pugh class A to B. The combination of PT and ALBI score before TACE had high predictive ability for liver dysfunction from Child–Pugh class A to B after TACE (specificity = 100%, sensitivity = 91.7%). The combined use of pre-TACE PT and ALBI score has a high predictive ability for liver dysfunction after TACE for Child–Pugh class A patients with HCC within up-to-seven criteria.

We hypothesized that, compared with young males, young females have a smaller decrease in blood flow to the inactive limb, accompanied by a smaller increase in arterial blood pressure, during dynamic exercise with increased inspiratory muscle work. Young males and females performed dynamic knee-extension and -flexion exercises for 10 min (spontaneous breathing for 5 min and voluntary hyperpnoea with or without inspiratory resistance for 5 min). Mean arterial blood pressure (MAP) and mean blood flow (MBF) in the brachial artery were continuously measured by means of finger photoplethysmography and Doppler ultrasound, respectively. No sex differences were found in the ΔMAP and ΔMBF (Δ: from baseline) during exercise without inspiratory resistance. In contrast, the ΔMAP during exercise with inspiratory resistive breathing was greater (P0.05) in males (+31.3 ± 2.1 mmHg, mean ± SE) than females (+18.9 ± 3.2 mmHg). The MBF during exercise with inspiratory resistance did not change in males (-4.4 ± 10.6 mL/min), whereas it significantly increased in females (+25.2 ± 15.4 mL/min). These results suggest that an attenuated inspiratory muscle-induced metaboreflex in young females affects blood flow distribution during submaximal dynamic leg exercise.

We aimed to prospectively identify the risk factors of sarcopenia in patients with cirrhosis. Patients (n = 193) included in a discovery cohort (January 2011 and December 2014) were categorized into alcoholic (A1; n = 55) and non-alcoholic cirrhosis (NA; n = 138) groups, and those (n = 235) in a validation cohort (January 2015 to December 2019) were categorized into alcoholic (n = 92), non-alcoholic steatohepatitis-related (n = 27), and hepatitis C virus-related cirrhosis groups (n = 116). Skeletal muscle mass index (SMI) was determined using computed tomography (SMI-CT) and bioelectrical impedance analysis (SMI-BIA). Endotoxin activity (EA) was measured with an EA assay. SMI-CT correlated with grip strength in all the groups but significantly correlated with SMI-BIA of the men in group A1 (R = 0.64, P

Introduction: Smaller muscle size and higher adipose tissue ratio of the quadriceps femoris are often observed after stroke. However, it is unclear whether muscle size and the intramuscular fat ratio of the quadriceps measured with ultrasonography (US) reflect gait independence in individuals with mild or severe hemiparetic stroke. Objective: The present study was performed to examine the relationships of gait independence with muscle thickness (MT) and echo intensity (EI) of the quadriceps femoris in individuals with hemiparesis after stroke. Methods: We examined 43 individuals with hemiparetic stroke. We assessed functional independence measure (FIM) gait scores and measured thickness and EI of the quadriceps using US. The relationships of FIM gait scores with MT and EI were examined using Spearman’s correlation coefficients in mild (n = 21) and severe (n = 22) hemiparetic stroke groups. Results: In the mild hemiparetic group, FIM gait scores were correlated with paretic limb MT (rho = 0.60, p < 0.01) and EI (rho = −0.57, p < 0.01). In the severe hemiparetic group, FIM gait scores were correlated with paretic limb MT (rho = 0.67, p < 0.01) and EI (rho = −0.43, p < 0.05), as well as non-paretic limb MT (rho = 0.86, p < 0.01) and EI (rho = −0.56, p < 0.01). Conclusions: Quadriceps thickness and EI were associated with the degree of gait independence. Atrophy and increased intramuscular fat of the quadriceps may be limiting factors for achieving gait independence.

Aims: Thrombocytopenia is a common complication among patients with chronic liver disease (CLD). To increase platelet counts, lusutrombopag, a small-molecule, second-generation thrombopoietin receptor agonist, was developed in September 2015. Lusutrombopag is mainly used in patients with platelet counts Methods: We evaluated 36 patients who received lusutrombopag for CLD. Changes in platelet counts were evaluated. A treatment response was defined as an increasing platelet count ≥20,000/µL from baseline after drug administration. The differences related to these changes between platelet counts ≥50,000 and Results: Of the patients, 25 had platelet counts ≥50,000/µL. The increase in platelet count and the date in which it reached a maximum did not significantly differ between the groups. The effectiveness of lusutrombopag did not significantly differ between the groups. In both groups, no adverse reaction was observed during lusutrombopag administration. Conclusion: In this study, we showed the effectiveness of lusutrombopag, which had no complications. This study is the first to report that the effectiveness of lusutrombopag was the same for patients with platelet counts ≥50,000/µL and

This study was performed to identify factors that discriminate muscle echo intensity (EI) among parameters of body composition, physical function and daily physical activity in elderly individuals. A total of 209 men and women (73.7 ± 2.8 y) were evaluated. EI was measured on ultrasonographic axial thigh muscle images. The participants were categorized into the low, mid and high EI groups. We measured the skeletal muscle mass index (SMI) and physical functions. The high EI group exhibited a significantly lower SMI, slower 5-m walking time and shorter 6-min walking distance than the low EI group and had a shorter moderate-intensity activity time than the mid EI group. As a result of the discriminant analysis, elderly individuals were categorized into EI groups by SMI, daily activity and physical function. The data indicate that morphologic and functional parameters and the daily activity level help to discriminate higher and lower muscle EI.

AIM To identify laboratory predictors of histological progression (HP) of primary biliary cholangitis (PBC). METHODS Sequential biopsies were carried out on 35 (11.4%) of 308 patients with PBC treated with ursodeoxycholic acid (UDCA). Patients were divided into high γ-glutamyl transpeptidase (GGT) (n = 18) and low GGT (n = 17) groups, based on the median value of GGT at baseline. Patients were then categorized as showing HP (progressive group, PG) or lacking HP (non-progressive group, NPG) according to the Scheuer and Nakanuma classifications, with the latter grading liver fibrosis (fibrosis score) and bile duct loss (BDL score). RESULTS According to the Scheuer definition, 12 patients had HP and 23 did not. According to the Nakanuma definition, 8 and 27 patients were in the PG and NPG groups, respectively. The fibrosis and BDL scores progressed in 13 and 8 patients, respectively, whereas 22 and 25 patients did not show HP, respectively. Fisher's exact probability test analysis revealed that the rate of HP using the Nakanuma fibrosis score was significantly higher in the high GGT group compared to the low GGT group (P

Acetone, which is exhaled with breath, is a by-product of lipolysis and could be used as a simple, useful indicator of lipolysis in the body because, unlike blood sampling, it can be measured non-invasively and repeatedly. Breath acetone concentration, however, is known to be affected by several factors such as exercise and food. We designed the experiments to evaluate the mixed effect on breath acetone of exercise and food ingestion in order to enhance the usefulness of breath acetone for monitoring fat loss. Seven healthy males performed moderate exercise for twice of 45 min with an interval of 15 min then rested for 4 h. Exhaled air was sampled every 15 min throughout the experiment. The subjects took one of four types, sugar-rich, balanced, protein-rich and fat-rich, of food for lunch one hour after the exercises or kept fasting. In the case of fasting, breath acetone kept increasing significantly (p < 0.05) compared with the rest value after the exercises until the end of the experiment. In contrast, in the case of taking any type of food, the change in breath acetone varied according to the food type. In the case of taking sugar-rich food, breath acetone significantly decreased (p < 0.05) compared with the fasting case. This decrease might be due to a suppression of acetone production when carbohydrates such as sugar are supplied to a body in the fasting condition. In contrast, in the case of taking fat-rich food, breath acetone showed the higher level than the fasting case. This additional increase might be attributable to the promotion of ketone bodies production, including acetone, due to the ingestion of medium chain triglycerides contained in the fat-rich food. We should therefore consider exercise and food ingestion in using breath acetone as a non-invasive indicator of lipolysis.

Background: This study aimed to compare the diagnostic performance of carbohydrate-deficient transferrin (CDT) and gamma-glutamyltranspeptidase (γ-GTP) to assess the single and combined benefits of these biological markers for the detection of chronic excessive alcohol consumption in patients with alcoholic cirrhosis. Methods: Biological markers were determined in blood samples from patients with alcoholic cirrhosis (drinking group, n = 35, nondrinking group, n = 81). The prediction accuracy of %CDT alone, γ-GTP alone, and their combination for the detection of excessive alcohol consumption was determined in patients with alcoholic cirrhosis. Results: Serum total bilirubin, alanine aminotransferase, aspartate aminotransferase, γ-GTP, and alkaline phosphatase levels and %CDT were significantly higher and serum albumin levels were significantly lower in the drinking group than in the nondrinking group. The combination of %CDT and γ-GTP compared with %CDT or γ-GTP alone showed a higher prediction accuracy. The combination of %CDT and γ-GTP exhibited a higher specificity than γ-GTP alone. However, in terms of sensitivity, no significant difference was found between single or combined markers. Conclusions: The combination of %CDT and γ-GTP is considered a useful biomarker of chronic excessive alcohol consumption in patients with alcoholic cirrhosis.

Background: Physical exercise is suggested to be effective for preventing cognitive decline in older adults, but the relative efficacy of different types of exercise have yet to be clarified. Objective: This single-blinded randomized controlled trial was designed to investigate the differential effects of aerobic exercise training (AT), resistance exercise training (RT), and combined exercise training (CT) on cognition in older adults with subjective memory complaints (SMC). Methods: Community-dwelling older adults with SMC (n = 415; mean age = 72.3 years old) were randomly assigned to one of the four groups: AT, RT, CT, or control group. The study consisted of two phases: a 26-week intervention and a 26-week follow-up. The participants were evaluated at baseline, 26 weeks (postintervention), and 52 weeks (follow-up). The primary outcome of this study was memory function, which was assessed using the Logical Memory II subtest of the Wechsler Memory Scale-Revised (WMS-R) score. The secondary outcomes included global cognitive function, verbal fluency, working memory, processing speed, and executive functions. Results: Intention-to-treat analysis by a mixed-effect model repeated measure showed that the AT group had significantly improved performance on the WMS-R Logical Memory II test (2.74 [1.82–3.66] points) than the control group (1.36 [0.44–2.28] points) at the postintervention assessment (p = 0.037). The effect was more pronounced in those without amnesia than those with amnesia. No significant improvement was observed in the RT and CT groups. Conclusion: This study suggests that AT intervention can improve delayed memory in community-dwelling older adults, particularly in individuals without objective memory decline.

Molecular targeted therapy with lenvatinib is commonly offered to advanced hepatocellular carcinoma (HCC) patients, although it is often interrupted by adverse effects which require a reduction in the initial dose. Thus, an alternative lenvatinib-based therapy to compensate for dose reduction is anticipated. This study aimed to assess the effect of combination of low-dose of lenvatinib and the angiotensin-II (AT-II) receptor blocker losartan on human HCC cell growth. In vitro studies found that losartan suppressed the proliferation by inducing G1 arrest and caused apoptosis as indicated by the cleavage of caspase-3 in AT-II-stimulated HCC cell lines (Huh-7, HLE, and JHH-6). Losartan attenuated the AT-II-stimulated production of vascular endothelial growth factor-A (VEGF-A) and interleukin-8 and suppressed lenvatinib-mediated autocrine VEGF-A production in HCC cells. Moreover, it directly inhibited VEGF-mediated endothelial cell growth. Notably, the combination of lenvatinib and losartan augmented the cytostatic and angiostatic effects of the former at a low-dose, reaching those achieved with a conventional dose. Correspondingly, a HCC tumor xenograft assay showed that the oral administration of losartan combined with lenvatinib reduced the subcutaneous tumor burden and intratumor vascularization in BALB/c nude mice. These findings support that this regimen could be a viable option for patients intolerant to standard lenvatinib dosage., 博士（医学）・甲第813号・令和4年3月15日, © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).

NEW FINDINGS What is the central question of this study? Increased respiratory muscle activation is associated with neural and cardiovascular consequences via the respiratory muscle-induced metaboreflex. Does ageing and/or sex influence the arterial blood pressure response during voluntary normocapnic incremental hyperpnoea? What is the main finding and its importance? The increase in blood pressure during hyperpnoea was smaller in younger females than in older females, whereas no difference was found between older males and older females. The blunted respiratory muscle-induced metaboreflex in younger females is normalized with advancing age, whereas ageing has no such effect in males. ABSTRACT We hypothesized that older females (OF) have a greater arterial blood pressure response to increased respiratory muscle work compared with younger females (YF) and that no such difference exists between older males (OM) and younger males (YM). To test these hypotheses, cardiovascular responses during voluntary normocapnic incremental hyperpnoea were evaluated and compared between older and younger subjects. An incremental respiratory endurance test (IRET) was performed as follows: target minute ventilation was initially set at 30% of the maximal voluntary ventilation (MVV12) and was increased by 10% of MVV12 every 3 min. The test was terminated when the subject could not maintain the target percentage of MVV12. Heart rate and mean arterial blood pressure (MAP) were recorded continuously. The increase in MAP from baseline (ΔMAP) during the IRET in OM (+24.0 ± 14.7 mmHg, mean ± SD) did not differ (P = 0.144) from that in YM (+24.3 ± 13.4 mmHg), but it was greater (P = 0.004) in OF (+31.2 ± 11.6 mmHg) than in YF (+10.3 ± 5.5 mmHg). No significant difference in ΔMAP during the IRET was observed between OM and OF (P = 0.975). These results suggest that the respiratory muscle-induced metaboreflex is blunted in YF, but it could be normalized with advancing age. In males, ageing has little effect on the respiratory muscle-induced metaboreflex. These results show no sex difference in the respiratory muscle-induced metaboreflex in older adults.

A potential restriction of the Baveno VI consensus, which helps to avoid unnecessary endoscopies, is the limited availability of FibroScan. We aimed to identify serum fibrosis indices that might aid in ruling out the presence of high-risk varices in cirrhotic patients. This retrospective study included 541 consecutive patients with cirrhosis who underwent endoscopy and had data available for nine serum fibrosis indices, including platelet count, hyaluronic acid, 7S fragment of type 4 collagen, procollagen type III N-terminal peptide, tissue inhibitor of metalloproteinases 1, Mac-2 binding protein glycosylation isomer, fibrosis index based on four factors (FIB-4), aspartate transaminase/platelet ratio index and enhanced liver fibrosis score. Optimal index cutoffs for predicting high-risk varices were calculated in an estimation cohort (n = 127) and evaluated in a validation cohort (n = 351). The diagnostic performance of the indices was assessed by receiver operating characteristic curve analysis. In the estimation cohort, a FIB-4 cutoff of 2.78 provided the greatest diagnostic accuracy in predicting both all-grade and high-risk varices. FIB-4 had a negative predictive value of 1.00 for high-risk varices in both cohorts, and 21.3% (27/127) and 14.8% (52/351) of the estimation and validation cohorts, respectively, avoided esophagogastroduodenoscopy, no high-risk varices were missed in either cohort. FIB-4 correctly identifies the absence of high-risk varices in patients with cirrhosis. Therefore, those with a FIB-4 of &ge, 2.78 should undergo esophagogastroduodenoscopy, and FIB-4 determination should be recommended every 6&ndash, 12 months concurrently with the other blood tests until the index value reaches 2.78 in those with a FIB-4 of &lt, 2.78.

The electromyographic (EMG) activity and force relationship, i.e. EMG-force relationship, is a valuable indicator of the degree of the neuromuscular activation during isometric force production. However, there is minimal information available regarding the EMG-force relationship of individual triceps brachii (TB) muscles at different elbow joint angles. This study aimed to compare the EMG-force relationships of the medial (TB-Med), lateral (TB-Lat), and long heads (TB-Long) of the TB. 7 men and 10 women performed force matching isometric tasks at 20%, 40%, 60%, and 80%maximum voluntary contraction (MVC) at 60°, 90°, and 120° of extension. During the submaximal force matching tasks, the surface EMG signals of the TB-Med, TB-Lat, and TB-Long were recorded and calculated the root mean square (RMS). RMS of each force level were then normalized by RMS at 100%MVC. For the TB-Med, ultrasonography was used to determine the superficial region of the muscle that faced the skin surface to minimize cross-talk. The joint angle was monitored using an electrogoniometer. The elbow extension force, elbow joint angle, and surface EMG signals were simultaneously sampled at 2 kHz and stored on a personal computer. The RMS did not significantly differ between the three muscles, except between the TB-Med and TB-Lat during 20%MVC at 60°. The RMS during force levels of ≥ 60%MVC at 120° was significantly lower than that at 60° or 90° for each muscle. The sum of difference, which represents the difference in RMS from the identical line, did not significantly differ in any of the assessed muscles in the present study. This suggests that a relatively smaller neuromuscular activation could be required when the elbow joint angle was extended. However, neuromuscular activation levels and relative force levels were matched in all three TB synergists when the elbow joint angle was at 90° or a more flexed position.

We hypothesized that respiratory muscle endurance training (RMET) in hypoxia induces greater improvements in respiratory muscle endurance with attenuated respiratory muscle metaboreflex and consequent whole-body performance. We evaluated respiratory muscle endurance and cardiovascular response during hyperpnoea and whole-body running performance before and after RMET in normoxia and hypoxia.Twenty-one collegiate endurance runners were assigned to control (n = 7), normoxic (n = 7), and hypoxic (n = 7) groups. Before and after the 6 wk of RMET, incremental respiratory endurance test and constant exercise tests were performed. The constant exercise test was performed on a treadmill at 95% of the individual's peak oxygen uptake (V˙O2peak). The RMET was isocapnic hyperpnoea under normoxic and hypoxic conditions (30 min·d). The initial target of minute ventilation during RMET was set to 50% of the individual maximal voluntary ventilation, and the target increased progressively during the 6 wk. Target arterial oxygen saturation in the hypoxic group was set to 90% in the first 2 wk, and thereafter it was set to 80%.Respiratory muscle endurance was increased after RMET in the normoxic and hypoxic groups. The time to exhaustion at 95% V˙O2peak exercise also increased after RMET in the normoxic (10.2 ± 2.4 to 11.2 ± 2.6 min) and hypoxic (11.5 ± 2.6 to 12.6 ± 3.0 min) groups, but not in the control group (9.6 ± 3.2 to 9.4 ± 4.0 min). The magnitude of these changes did not differ between the normoxic and the hypoxic groups (P = 0.84).These results suggest that the improvement of respiratory muscle endurance and blunted respiratory muscle metaboreflex could, in part, contribute to improved endurance performance in endurance-trained athletes. However, it is also suggested that there are no additional effects when the RMET is performed in hypoxia.

We aimed to test the hypothesis that the magnitude of differences in muscle activation of the knee and hip extensor muscles between high-intensity interval exercise (HIE) and moderate-intensity constant exercise (CE) would be greater for the gluteus maximus than for the quadriceps femoris muscle. Participants were 11 male middle- or long-distance runners. The HIE (4 sets, 4-min induration, performed at 80–85%VO2peak and followed by a 3-min period of cycling at

Introduction: Quadriceps muscle atrophy and quality loss, defined as an increased ratio of intramuscular fat and/or connective tissue, are often observed especially in the paretic limb of post-stroke patients. This study was performed to examine the relationship of quadriceps muscle thickness (MT) with muscle echo intensity (EI) and the severity of motor paralysis after stroke. Methods: Thirty-six hemiparetic subacute post-stroke patients were enrolled. We examined the MT (index of muscle quantity) and the EI (index of muscle quality) at the anterior mid-thigh in both limbs. We also assessed the Brunnstrom stage (BR stage), subcutaneous adipose tissue thickness, time since stroke, age, body weight, sex, number of medications, and nutritional and inflammation status. Results: The MT in the paretic limb was explained by the BR stage (β = –0.26, p < 0.01), body weight (β = 0.68, p < 0.01), and serum albumin (β = 0.34, p < 0.01), with an adjusted R2 of 0.81. The MT in the non-paretic limb was explained by the muscle EI (β = –0.55, p < 0.01) and age (β = –0.40, p < 0.01), with an adjusted R2 of 0.69. The muscle EI was explained by the MT in the paretic limb (β = –0.34, p < 0.01) and non-paretic limb (β = –0.69, p < 0.01). Conclusions: Our results suggest that motor paralysis, aging, and malnutrition contribute to quadriceps atrophy in post-stroke patients. Moreover, a potential countermeasure to diminish muscle quality loss is maintenance of muscle quantity.