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The present study examined the effects of daily activities of the hands on finger motor function in older adults. Maximum tapping frequency with each finger during single-finger tapping and alternate movements of index–middle, middle–ring, and ring–little finger pairs during double-finger tapping were compared between older adults who used their hands actively in their daily lives and those who did not. The active participants had significantly faster tapping rates for the ring finger in the single-finger tapping and the middle–ring finger pair in the double-finger tapping than did the inactive participants. Thus, daily activity of the hands in older adults could be effective at preventing the loss of dynamic motor function in individual fingers, especially with greater difficulty in movement, resulting from the degeneration with age.

We investigated the impact of C-reactive protein to albumin ratio (CAR) on predicting outcomes in 522 patients with unresectable hepatocellular carcinoma (HCC) treated with lenvatinib. We determined the optimal CAR cutoff value with time-dependent receiver operating characteristic curve analysis. Additionally, we clarified the relationship between CAR and liver function or HCC progression. Median overall survival was 20.0 (95% confidence interval (CI), 17.2–22.6) months. The optimal CAR cutoff value was determined to be 0.108. Multivariate analysis showed that high CAR (≥0.108) (hazard ratio (HR), 1.915; 95% CI, 1.495–2.452), Eastern Cooperative Oncology Group performance status ≥1 (HR, 1.429), and α-fetoprotein ≥400 ng/mL (HR, 1.604) were independently associated with overall survival. Cumulative overall survival differed significantly between patients with low versus high CAR (p

AIM We aimed to compare the well-established liver fibrosis (LF) markers in Japanese patients with chronic hepatitis B (CHB, n = 331) and chronic hepatitis C (CHC, n = 886) and to discuss possible causes of differences in results between CHB patients and CHC patients. METHODS Virtual touch quantification (VTQ) in acoustic radiation force impulse, Fibrosis-4 (Fib-4) index, aspartate aminotransferase to platelet ratio index (APRI), and hyaluronic acid (HA) were compared between the two cohorts. As an additional investigation, total collagen proportional area (TCPA, %) was tested using liver pathological samples (n = 83). RESULTS Significant LF (F2 or greater) and advanced LF (F3 or greater) were identified in 153 (46.2%) and 76 (23.0%) patients in the CHB cohort and 579 (65.3%) and 396 (44.7%) patients in the CHC cohort. The median VTQ, Fib-4 index, APRI, and HA values in the CHB cohort were 1.20 m/s, 1.36, 0.44, and 25 ng/mL; those in the CHC cohort were 1.32 m/s, 2.60, 0.74, and 65.5 ng/mL (P-values, all

Background/Aim: Hepatocellular carcinoma patients (HCC) related with non-alcoholic steatohepatitis (NASH) has been recently reported to be not responsive to immune-checkpoint inhibitor treatment (ICI). This study aimed to evaluate therapeutic efficacy in non-alcoholic fatty liver disease (NAFLD)/NASH-related unresectable-HCC (u-HCC) treated with lenvatinib.Material/Methods: Five-hundred-thirty u-HCC with Child-Pugh A were enrolled, and divided into the NAFLD/NASH (n=103) and Viral/Alcohol (n=427) groups. Clinical features were compared in a retrospective manner.Results: Progression-free survival (PFS) was better in the NAFLD/NASH than the Viral/Alcohol group (median 9.3 vs. 7.5 months, P=0.012), while there was no significant difference in overall survival (OS) (20.5 vs. 16.9 months, P=0.057). In Cox-hazard analysis of prognostic factors for PFS, elevated AFP (≥400ng/mL) (HR1.294, P=0.014), elevated ALT (≥30 U/L) (HR1.247, P=0.029), modified ALBI grade 2b (HR1.236, P=0.047), and NAFLD/NASH etiology (HR0.763, P=0.036) were significant prognostic factors. NAFLD/NASH etiology was not a significant prognostic factor in Cox-hazard analysis for OS (HR0.750, P=0.076), whereas AFP (≥400ng/mL) (HR1.402, P=0.009), later line use (HR0.737, P=0.0137), BCLC C stage (HR1.297, P=0.035), and modified ALBI grade 2b (HR1.875, P

Introduction: Immune checkpoint inhibitors (ICIs) are promising agents for the treatment of hepatocellular carcinoma (HCC). However, the establishment of noninvasive measure that could predict the response to ICIs is challenging. This study aimed to evaluate tumor responses to ICIs using the hepatobiliary phase of gadolinium-ethoxybenzyl-diethylenetriamine (Gd-EOB-DTPA)-enhanced magnetic resonance imaging (MRI), which was shown to reflect Wnt/β-catenin activating mutation. Methods: A total of 68 intrahepatic HCC nodules from 18 patients with unresectable HCC and Child-Pugh class A liver function who received anti-programmed cell death 1 (PD-1)/programmed death-ligand 1 (PD-L1) monotherapy were enrolled in this study. All patients had viable intrahepatic lesions evaluable using the hepatobiliary phase of Gd-EOB-DTPA-enhanced MRI within the 6 months prior to the treatment. The relative enhancement ratio was calculated, and the time to nodular progression (TTnP) defined as 20% or more increase in each nodule was compared between higher or hypo-enhancement HCC nodules. Then, the progression-free survival (PFS) and objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) were compared between patients with and without HCC nodules with higher enhancement on hepatobiliary phase images. Results: The median PFS was 2.7 (95% confidence interval [CI]: 1.4–4.0) months in patients with HCC nodules with higher enhancement (n = 8) and 5.8 (95% CI: 0.0–18.9) months in patients with hypointense HCC nodules (n = 10) (p = 0.007). The median TTnP of HCC nodules with higher enhancement (n = 23) was 1.97 (95% CI: 1.86–2.07) months and that of hypointense HCC nodules (n = 45) was not reached (p = 0.003). The ORR was 12.5% (1/8) versus 30.0% (3/10); the disease control rate was 37.5% (3/8) versus 70.0% (7/10), respectively, in patients with or without higher enhancement intrahepatic HCC nodules. Conclusion: The TTnP on HCC nodules with higher enhancement and the median PFS in patients who carried higher enhancement intrahepatic HCC nodules were significantly shorter than those in hypointense HCC nodules with anti-PD-1/PD-L1 monotherapy. The intensity of the nodule on the hepatobiliary phase of Gd-EOB-DTPA-enhanced MRI is a promising imaging biomarker for predicting unfavorable response with anti-PD-1/PD-L1 monotherapy in patients with HCC.

Although programmed cell death protein 1 (PD&minus, 1)/PD-ligand 1 (PD-L1) blockade is effective in a subset of patients with hepatocellular carcinoma (HCC), its therapeutic response is still unsatisfactory. Alternatively, the potential impact of the lenvatinib in patients who showed tumor progression on PD&minus, 1/PD-L1 blockade is unknown. In this work, we evaluated the safety and efficacy of lenvatinib administration after PD-1/PD-L1 checkpoint blockade. The outcome and safety of lenvatinib administered after PD-1/PD-L1 blockade failure was analyzed retrospectively in 36 patients. Tumor growth was assessed every 4&ndash, 8 weeks using modified Response Evaluation Criteria in Solid Tumors. The mean relative dose intensity of lenvatinib was 87.6% and 77.8% in patients receiving a starting dose of 8 (interquartile range (IQR), 77.5&ndash, 100.0) mg and 12 (IQR, 64.4&ndash, 100.0) mg, respectively. Since lenvatinib therapy initiation, the median progression-free survival was 10 months (95% confidence interval (CI): 8.3&ndash, 11.8) and the median overall survival was 15.8 months (95% CI: 8.5&ndash, 23.2). The objective response rate was 55.6%, and the disease control rate was 86.1%. No particular safety concerns were observed. Lenvatinib demonstrated considerable antitumor effects with acceptable safety in patients with progressive and unresectable HCC when administered right after PD-1/PD-L1 blockade failure.

Whether direct-acting antiviral (DAA) therapy can reduce liver fibrosis and steatosis in patients with chronic hepatitis C virus (HCV) infection remains unclear. We evaluated sequential changes in liver stiffness and steatosis using transient elastography (TE) and the TE-based controlled attenuation parameter (CAP) in patients with HCV who received DAA therapy.A total of 57 patients with HCV who received DAA therapy and achieved sustained virological response (SVR) were analyzed. Liver stiffness as evaluated with TE, steatosis as evaluated with CAP, and laboratory data were assessed before treatment (baseline), at end of treatment (EOT), 24 weeks after EOT (SVR24), and 48 weeks after EOT (SVR48).Alanine aminotransferase levels, corresponding to the presence of necroinflammatory activity, significantly decreased overall, with significant differences between baseline and EOT, EOT, and SVR24, and baseline and SVR48. However, alanine aminotransferase levels showed no significant changes between SVR24 and SVR48. Median (interquartile range) liver stiffness values at baseline, EOT, SVR24, and SVR48 were 8.3 (5.0-14.8), 7.4 (4.6-14.7), 5.3 (4.1-11.8), and 5.4 (4.0-13.4) kPa, respectively (baseline vs. EOT, P=0.044; EOT vs. SVR24, P=0.011; and SVR24 vs. SVR48, P=0.054). In patients with fatty liver (CAP≥236 dB/m, n=14), CAP values at baseline and SVR48 were 253 (245-278) and 229 (209-249) dB/m, respectively (P=0.020).Liver stiffness at SVR24 might reflect liver fibrosis in the patients who received DAA therapy and achieved SVR. In addition, liver steatosis reduces in the same cohort with fatty liver.

AIM Presently, no standardized definition or acceptable diagnostic criteria have been established for acute presentation of autoimmune hepatitis (AP-AIH), making it difficult to differentiate that condition from drug-induced liver injury (DILI). This study aimed to characterize clinical and histological features for distinguishing between AP-AIH and DILI. METHODS Clinical, biochemical, and histological characteristics of AP-AIH and DILI in clinically well-characterized cases were compared in a standardized manner to clarify differences. RESULTS In clinical evaluations, immunoglobulin G level and rate of anti-nuclear antibody positivity were greater in AP-AIH than DILI cases. As for diagnosis of each condition, significant (P

Although transcatheter arterial chemoembolization (TACE) is the standard of care for intermediate-stage hepatocellular carcinoma (HCC), this is a largely heterogeneous disease that includes a subgroup of patients who do not benefit from TACE. The treatment strategy for this subgroup of patients currently remains an unmet need in clinical practice. Here, we performed a proof-of-concept study that lenvatinib may be a more favorable treatment option over TACE as an initial treatment in intermediate-stage HCC patients with large or multinodular tumours exceeding the up-to-seven criteria. This proof-of-concept study included 642 consecutive patients with HCC initially treated with lenvatinib or conventional TACE (cTACE) between January 2006 and December 2018. Of these patients, 176 who received lenvatinib or cTACE as an initial treatment and met the eligibility criteria (unresectable, beyond the up-to-seven criteria, no prior TACE/systemic therapy, no vascular invasion, no extrahepatic spread and Child&ndash, Pugh A liver function) were selected for the study. Propensity score matching was used to adjust for patient demographics. After propensity-score matching, the outcome of 30 patients prospectively treated with lenvatinib (14 in clinical trials, one in an early access program and 15 in real world settings) and 60 patients treated with cTACE as the initial treatment was compared. The change of albumin-bilirubin (ALBI) score from baseline to the end of treatment were &minus, 2.61 to &minus, 2.61 for 30 patients in the lenvatinib group (p = 0.254) and &minus, 2.66 to &minus, 2.09 in the cTACE group (p &lt, 0.01), respectively. The lenvatinib group showed a significantly higher objective response rate (73.3% vs. 33.3%, p &lt, 0.001) and significantly longer median progression-free survival than the cTACE group (16.0 vs. 3.0 months, 0.001). Overall survival was significantly longer in the lenvatinib group than in the cTACE group (37.9 vs. 21.3 months, hazard ratio: 0.48, p &lt, 0.01). In patients with large or multinodular intermediate-stage HCC exceeding the up-to-seven criteria with Child&ndash, Pugh A liver function, who usually do not benefit from TACE, lenvatinib provides a more favorable outcome than TACE.

522 Background: Intermediate-stage HCC is a heterogenous population with subgroups of patients that do not benefit from TACE. Hence, we conducted a matched cohort study to compare the efficacy of lenvatinib to TACE in intermediate-stage HCC patients with large or multinodular tumours exceeding the up-to-7 criteria. Methods: This study first identified 642 consecutive patients with HCC initially treated with lenvatinib or conventional TACE (cTACE) between January 2006 and December 2018. Of these patients, 176 who received lenvatinib or cTACE as an initial treatment and met the eligibility criteria [unresectable, beyond the up-to-7 criteria, without prior TACE/systemic therapy, no vascular invasion, no extrahepatic spread and Child-Pugh A liver function] were selected. Propensity score matching was used to adjust for patients’ demographics. Results: After propensity-score matching, outcome of 30 patients prospectively treated with lenvatinib (14 in clinical trials [1 Phase II and 13 Phase III REFLECT trial], 1 in early access program and 15 in real world setting) and 60 patients treated with cTACE as the initial treatment was compared. The lenvatinib group showed a higher objective response rate (73.3% vs. 33.3%; p < 0.001) and longer median progression-free survival than the cTACE group (16.0 vs. 3.0 months; p < 0.001). Median overall survival was also significantly longer in the lenvatinib group than in the cTACE group (37.9 vs. 21.3 months; hazard ratio: 0.48, p < 0.01). The change of ALBI score from baseline to the end of treatment were -2.61 to -2.61 for 30 patients in lenvatinib group (p = 0.254) and -2.66 to -2.09 in cTACE group (p < 0.01), respectively. Conclusions: In patients with large or multinodular intermediate-stage HCC exceeding the up-to-7 criteria with Child-Pugh A liver function, who usually do not benefit from TACE, lenvatinib is associated with better outcome than TACE. In particular, leventinib is associated with preservation of hepatic function during treatment while TACE is associated with deterioration of hepatic function.

Aim Alcoholic hepatocellular carcinoma (ALD-HCC) accounts for the majority of non-B non-C HCC (NBNC-HCC) cases. Although alcohol is a potent carcinogen, there have been few reports on the influence of modest alcohol consumption in NBNC-HCC. This study aimed to investigate the clinical characteristics and prognosis of NBNC-HCC patients with modest alcohol consumption. Methods From 2007 to 2010, 2283 HCC patients were evaluated at 10 hospitals. We collected detailed etiology data of 588 NBNC-HCC patients and compared the clinical characteristics and prognosis between ALD-HCC and modest alcohol-HCC patients. Results There were 69 HCC patients with modest alcohol consumption, accounting for 3% of all HCC patients evaluated. This patient group had significantly more women and higher prevalence of Child–Pugh class A, hypertension and advanced disease stage, and were diagnosed with HCC at an older age than the ALD-HCC group (266 patients). Additionally, among the modest alcohol-HCC patients, diabetes was significantly more common in the anti-hepatitis B core (HBc) negative subgroup than in the anti-HBc positive subgroup. However, no significant difference in survival was observed between the two patient groups regardless of significant differences in tumor staging. Alcohol consumption and metabolic factors were not significant independent predictors of survival. Conclusion The clinical characteristics of modest alcohol-HCC included advanced staging, favorable liver reserve capacity and older age at diagnosis. HCC development in patients with modest alcohol consumption may relate to metabolic factors. Although approximately 30% of the evaluated HCC cases were in advanced stages, the prognosis of NBNC-HCC patients with modest alcohol consumption was relatively favorable.

Background. Only a few biomarkers based on metabolic parameters for evaluating liver fibrosis have been reported. The aim of this study was to investigate the relevance of an index obtained from three metabolic variables (glycated albumin: GA, glycated hemoglobin: HbA1c, and branched-chain amino acids to tyrosine ratio: BTR) to the degree of liver fibrosis in hepatitis C virus virus- (HCV-) positive patients.Methods. A total of 394 HCV-positive patients were assessed based on the values of a new index (GA/HbA1c/BTR). The index findings were used to investigate the relationship with the degree of liver fibrosis.Results. The new index showed an association with the stage of fibrosis (METAVIR scores: F0-1: 0.42 ± 0.10, F2: 0.48 ± 0.15, F3: 0.56 ± 0.22, and F4: 0.71 ± 0.30). The index was negatively correlated with three variables of liver function: the prothrombin time percentage (P<0.0001), albumin level (P<0.0001), and cholinesterase level (P<0.0001). The new index showed a higher correlation related to liver function than FIB-4 and the APRI did. In addition, the index showed a higher AUROC value than that of FIB-4 and the APRI for prediction of liver cirrhosis.Conclusion. The new metabolism-related index, GA/HbA1c/BTR value, is shown to relate to the degree of liver fibrosis in HCV-positive patients.

Background: This study investigated the impact of baseline liver function according to the Child&ndash, Pugh score and ALBI (albumin-bilirubin) grade on the outcomes of patients with unresectable hepatocellular carcinoma treated with lenvatinib. Methods: A total of 82 lenvatinib treated patients were included. The correlations of baseline liver function according to the Child&ndash, Pugh score and ALBI grade with treatment outcomes, including objective response rate per mRECIST (modified Response Evaluation Criteria in the Solid Tumor), time to treatment failure, treatment duration, and likelihood of treatment discontinuation due to adverse events, were assessed in patients with hepatocellular carcinoma treated with lenvatinib. Patients were divided into four groups: (1) Child&ndash, Pugh score 5 and ALBI grade 1 (group 1), (2) Child&ndash, Pugh score 5 and ALBI grade 2 (group 2), (3) Child&ndash, Pugh score 6 (group 3), and (4) Child&ndash, Pugh score &ge, 7 (group 4). Univariate and multivariate analyses were performed to identify the factors contributing to the objective response rate and likelihood of discontinuation due to adverse events. Results: Among the 82 patients analyzed, group 1 had the highest objective response rate (57.1%) and the lowest likelihood of treatment discontinuation because of adverse events (11.1%) among the four groups (p &lt, 0.05 and p &lt, 0.05). Multivariate analysis identified ALBI grade 1 and baseline AFP level &lt, 200 ng/mL as the significant predictors of a high objective response rate (p &lt, 0.01), and confirmed that patients with ALBI grade 1 had the lowest probability of treatment discontinuation due to adverse events (p &lt, 0.01). Conclusions: Patients with Child&ndash, Pugh score of 5 and ALBI grade 1 predicted a higher response rate and lower treatment discontinuation due to adverse events by lenvatinib treatment.

This study aimed to establish a new scoring system that combined several risk factors, including virtual touch quantification (VTQ) values and fasting plasma glucose (FPG) levels, for predicting the development of hepatocellular carcinoma (HCC) in patients with chronic liver disease. A total of 1808 chronic liver disease patients who underwent VTQ measurement were analyzed. Risk factors for developing HCC were selected by multivariate Cox proportional hazards models. VTQ (>1.33 m/s), FPG (≥110 mg/dl), sex (male), age (≥55 years), and α-fetoprotein (AFP) level (≥5 ng/ml) were independently selected as risk factors for HCC development by multivariate analysis. Using these parameters, we established a new scoring system (0 to 5 points), based on VTQ, FPG, sex, age, and AFP level, named VFMAP. As compared with the low VFMAP score group (0 or 1 point), the hazard ratio for the incidence of HCC was 17.37 [95 % confidence interval (CI), 2.35–128.40] in the intermediate-score group (2 or 3 points) and 66.82 (95 % CI, 9.01–495.80) in the high-score group (4 or 5 points). The area under the receiver operating characteristic curve of the VFMAP score for predicting HCC development within 5 years was 0.82 (95 % CI, 0.76–0.87), indicating a moderate diagnostic value. A VFMAP cutoff value of 3 excluded HCC within 5 years with a high negative predictive value (98.2 %). The VFMAP score accurately predicted HCC in patients with chronic liver disease.

We investigated the effects of moderate hypoxia (FiO2 = 15%) on different kinetics between pulmonary ventilation ([Formula: see text]) and heart rate (HR) during treadmill walking. Breath-by-breath [Formula: see text], oxygen uptake ([Formula: see text]), carbon dioxide output ([Formula: see text]), and HR were measured in 13 healthy young adults. The treadmill speed was sinusoidally changed from 3 to 6 km·h-1 with four oscillation periods of 1, 2, 5, and 10 min. The amplitude (Amp), phase shift (PS) and mean values of these kinetics were obtained by harmonic analysis. The mean values of all of these responses during walking at a sinusoidally changing speed became greater under hypoxia compared to normoxia (FiO2 = 21%), indicating that moderate hypoxia could achieve an increased energy expenditure (increased [Formula: see text] and [Formula: see text]) and hyperventilation. The Amp values of the [Formula: see text], [Formula: see text], and [Formula: see text] kinetics were not significantly different between normoxia and hypoxia at most periods, although a significantly smaller Amp of the HR was observed at faster oscillation periods (1 or 2 min).The PS of the HR was significantly greater under hypoxia than normoxia at the 2, 5, and 10 min periods, whereas the PS of the [Formula: see text], [Formula: see text], and [Formula: see text] responses was not significantly different between normoxia and hypoxia at any period. These findings suggest that the lesser changes in Amp and PS in ventilatory and gas exchange kinetics during walking at a sinusoidally changing speed were remarkably different from a deceleration in HR kinetics under moderate hypoxia.

Purpose: The maximum isometric force production capacity of the fingers decreases with age. However, little information is available on age-related changes in dynamic motor capacity of individual fingers. The purpose of this study was to compare the dynamic motor function of individual fingers between elderly and young adults using rapid single-finger and double-finger tapping. Methods: Fourteen elderly and 14 young adults performed maximum frequency tapping by the index, middle, ring, or little finger (single-finger tapping) and with alternate movements of the index-middle, middle-ring, or ring-little finger-pair (double-finger tapping). The maximum pinch force between the thumb and each finger, tactile sensitivity of each fingertip, and time taken to complete a pegboard test were also measured. Results: Compared with young subjects, the older subjects had significantly slower tapping rates in all fingers and finger-pairs in the tapping tasks. The age-related decline was also observed in the tactile sensitivities of all fingers and in the pegboard test. However, there was no group difference in the pinch force of any finger. The tapping rate of each finger did not correlate with the pinch force or tactile sensitivity for the corresponding finger in the elderly subjects. Conclusions: Maximum rate of finger tapping was lower in the elderly adults compared with the young adults. The decline of finger tapping ability in elderly adults seems to be less affected by their maximum force production capacities of the fingers as well as tactile sensitivities at the tips of the fingers.

Background and objective: Acid-induced lung injury from aspiration is one of the most important causes of ARDS. Calcitonin gene-related peptide (CGRP) is a neuropeptide that has various biological actions. The current study investigated whether CGRP might have pathophysiological roles in acid-induced lung injury. Methods: The investigations employed CGRP gene-disrupted mice––mutant mice (CGRP–/–) and their littermate controls (CGRP+/+). Anaesthetized and mechanically ventilated mice received 2 mL/kg HCl (pH = 1.5) intratracheally. Lung wet-to-dry weight ratios were calculated to assess pulmonary oedema, total and differential cell counts of the BALF were determined, and measurements of myeloperoxidase activity were performed. Results: Acid-induced lung injury was characterized by an increase in lung permeability and respiratory failure. Disruption of the CGRP gene significantly attenuated acid-induced injury, oedema and respiratory failure. Conclusions: This study suggests that CGRP is involved in the pathogenesis of acute lung injury caused by acid aspiration and CGRP mutant mice may provide an appropriate model to study molecular mechanisms in this context.

We studied the relationship between exercise hyperpnea (i.e., ventilatory dynamics) at the onset of exercise and hypercapnic ventilatory response (HCVR), and their differences between the follicular (FP) and luteal (LP) phases of the menstrual cycle in six healthy females. HCVR was tested under three O(2) conditions: hyperoxia (FiO(2)=1.0), normoxia (0.21), and hypoxia (0.12). HCVR was defined as the relationship between the end-tidal P(CO2) and minute ventilation (V(E)) using the regression line of the CO(2) slope and a mimetically apneic threshold of CO(2). HCVR provocation and measurements were conducted using an inspired CO(2) concentration of up to approximately 8 mmHg higher than the end-tidal P(CO2) level of basal isocapnic the end-tidal P(CO2) at each menstrual both the slope and threshold in HCVR showed no statistically significant difference between LP and FP under any inspired FiO(2) conditions. In the case of exercise hyperpnea during the onset of submaximal exercise, the mean response time (MRT) in V(E) dynamics showed no significant difference between LP and FP. Consequently, MRT in V(E) response was not related to the slope in HCVR. During steady-state exercise, even though the V(E)/V(CO2) showed no significance between LP and FP, V(E)/V(CO2) was significantly related to the slope in HCVR (r=0.59, P

Many studies of right/left differences in motor performance related to handedness have employed tasks that use arm movements or combined arm and hand movements rather than movements of the fingers per se, the well-known exception being rhythmic finger tapping. We therefore explored four simple tasks performed on a small touchscreen with relatively isolated movements of the index finger. Each task revealed a different right/left performance asymmetry. In a step-tracking Target Task, left-handed subjects showed greater accuracy with the index finger of the dominant left hand than with the nondominant right hand. In a Center-Out Task, right-handed subjects produced trajectories with the nondominant left hand that had greater curvature than those produced with the dominant right hand. In a continuous Circle Tracking Task, slips of the nondominant left index finger showed higher jerk than slips of the dominant right index finger. And in a continuous Complex Tracking Task, the nondominant left index finger showed shorter time lags in tracking the relatively unpredictable target than the dominant right index finger. Our findings are broadly consistent with previous studies indicating left hemisphere specialization for dynamic control and predictable situations vs. right hemisphere specialization for impedance control and unpredictable situations, the specialized contributions of the two hemispheres being combined to different degrees in the right vs. left hands of right-handed vs. left-handed individuals.

Background. In hepatitis B virus- (HBV-) positive patients, the relationship between the metabolic variables and histological degree of liver fibrosis has been poorly investigated. Methods. A total of 176 HBV-positive patients were assessed in whom the ratios of glycated albumin-to-glycated hemoglobin (GA/HbA1c) were calculated in order to investigate the relationship with the degree of liver fibrosis. Results. The GA/HbA1c ratio increased in association with the severity of fibrosis (METAVIR scores: F0-1: 2.61 ± 0.24, F2: 2.65 ± 0.24, F3: 2.74 ± 0.38, and F4: 2.91 ± 0.63). The GA/HbA1c ratios were inversely correlated with four variables of liver function: the prothrombin time (PT) percentage (P0.0001), platelet count (P0.0001), albumin value (P0.0001), and cholinesterase value (P0.0001). The GA/HbA1c ratio was positively correlated with two well-known markers of liver fibrosis, FIB-4 (P0.0001) and the AST-to-platelet ratio index (APRI) (P0.0001). Furthermore, the GA/HbA1c showed better correlations with two variables of liver function (PT percentage and cholinesterase value) than did FIB-4 and with all four variables than did the APRI. Conclusion. The GA/HbA1c ratio is associated with the degree of liver fibrosis in HBV-positive patients.

In orbital roof blow-up fractures, reduction can be achieved easily using an approach from the anterior cranial fossa but the procedure is highly invasive. In contrast, an orbital approach using a superior blepharoplasty incision is minimally invasive. However, if bone fragments are adhered to the dura mater, there is a risk of dura mater injury when fragments are moved for reduction. In blow-in fractures, reduction is performed by pushing the bone fragments against the anterior cranial fossa. In contrast, the procedure is difficult for blow-up fractures because bone fragments must be pulled out into the orbit through the anterior cranial fossa. Orbital blow-up fractures are often associated with intracranial injuries and frequently treated by an approach from the anterior cranial fossa. There has not yet been a report that discusses whether reduction of bone fragments should be performed in blow-up fracture without intracranial injury. In this report, we describe two cases of orbital roof blow-up fracture that did not require treatment for intracranial injury and that were treated using an orbital approach. The treatment involved only the release of orbital fat entrapped between bone fragments and did not involve reduction. The treatment outcomes were good in both cases.

The purpose of this study was to investigate the prevalence of playing-related musculoskeletal disorders (PRMDs) among Japanese female classical pianists of different age groups. The causal factors for PRMDs also were examined. A group of 203 senior pianists, including piano teachers and students with piano majors at high schools and colleges, were surveyed using questionnaires. Results showed that 77% of these pianists suffered from PRMDs in at least one of their body portions. This value was larger than those reported in Western countries. Forty-four percent of these were serious enough to warrant medical treatment, which was a lower rate than reported in Western countries. The difference in these numbers may reflect the current state of understanding of PRMDs among Japanese pianists and their educators. The prevalence of PRMDs was found to be age-dependent. In the student groups, the finger/hand had the highest rate of PRMDs, followed by the forearm and shoulder. The senior group, on the other hand, had the highest PRMD incidence at the neck/trunk, followed by the forearm and hand/finger. Care may need to be exercised for these differences. The results also indicated that prolonged daily practice (>4 hours), playing chords forcefully, eagerness about practice, and nervous traits were found to contribute to the development of PRMDs in these pianists. Hand size was, on the other hand, not a significant risk factor of PRMDs.

Using fast tapping tasks with each of the four fingers (single-finger tapping) and with two of the fingers used alternately (double-finger tapping), the ability to make rapid tapping movement by the individual fingers was compared between expert pianists and nonmusician controls in both genders. Maximal pinch and grasp forces were also measured to assess strength of individual fingers and whole hand, respectively. Movement of the ring and little fingers was slower than that of the index and middle fingers in both the pianists and controls. The slowness of the ring and little fingers was, however, much less evident in the pianists than the controls in both tapping tasks. The pianists also had smaller intertap interval variability for the index and middle fingers. No pianist–control difference was found for the pinch and grasp forces. Piano training, therefore, effectively changed the ability to move individual fingers rapidly, but not their flexor strength. No gender difference was found in any of the tapping tasks though males had greater strength. Gender thus does not appear to be a factor differentiating the ability to move individual fingers rapidly.

The purposes of this study were to assess differences among the index, middle, ring, and little fingers in dynamic motor function, using single-finger-tapping and double-finger-tapping tasks, and to investigate the effect of long-term training on dynamic motor function, using trained pianists. Four miniature strain gauge force transducers were used to measure the external force generated by each finger during tapping. Twelve healthy male adults and three female adult pianists tapped force transducers for 9 seconds as fast as possible, using their dominant right hands, while the other fingers contacted with the force transducers. In the single-finger tapping, we asked subjects to tap using each finger: index, middle, ring, and little finger. In the double-finger tapping, subjects performed alternating movements of a pair of fingers. A comparison among the four fingers in single-finger tapping revealed that the index and middle fingers attained significantly faster tapping, indicating the superiority of these two fingers over the other two fingers in terms of dynamic motor function. Changes in isometric forces generated by the non-tapping fingers accompanied the tapping finger movements; the correlation between tapping and non-tapping fingers was greater for the ring finger than for the other fingers. This suggests that the ring finger is more dependent on the movements of other fingers, especially neighboring fingers. Differences among the fingers in dynamic motor function could result from anatomical and neurophysiological factors. During two-finger movement, the dynamic motor function of each finger was affected by the combination of fingers. Finger combinations that are less used in ordinary life had lower tapping speeds than the other combinations. For pianists, tapping rates of the little and ring fingers in single-finger tapping were similar to those of the index and middle fingers. There was less accompanying force by non-tapping fingers of the pianists than of non-pianists. In double-finger tapping, tapping rates for any combination of fingers was nearly the same for the pianists. These suggested that long-term training could alter dynamic motor function of the fingers.

Two positron emission tomography (PET) studies were performed on 18 normal volunteers to investigate regional cortical and subcortical activation induced by the repetitive lifting-holding-replacing of an object using a precision grip between the index finger and thumb. A three-dimensional PET was performed using H215O as a tracer. The first study was aimed to investigate the brain areas involved in a grasp-lift-hold-replace action and the effect of object weight. Data were obtained for 10 subjects under three object weight conditions (4, 200, and 600 g) and a rest condition. Grip and lift forces on a similar object and the activity of selected muscles in the hand, arm, and shoulder were also recorded in separate lifting trials. An external auditory beep sounded every 3.5 seconds to initiate the lifting action. The subjects repeated the lifting action 20-22 times during each PET scanning. A comparison between all movement conditions and the rest condition revealed significant activation of the primary motor (M1), primary sensory (S1), dorsocaudal premotor (PM), caudal supplementary motor (SMA), and cingulate motor (CMA) cortices contralateral to the hand used. On the ipsilateral side, activation of the M1, caudal SMA, and inferior parietal (BA40) was found. In the subcortical areas, the hemispheres of the bilateral cerebellum, left basal ganglia, and thalamus were activated. Behavioral adaptation to a heavier object weight was revealed in a nearly proportional increase of both grip and lift forces, and a higher level of hand and arm muscle activities. An increase in the rCBF associated with these changes was noted in several cortical and subcortical areas. Consistent object-weight-dependent activation, however, was observed only in the M1/S1 contralateral to the hand used and to some extent in the ipsilateral cerebellum.The second study was aimed at investigating the brain areas involved in each of the preparatory and execution phases for lifting of an object. In addition, the difference in brain activation between right (dominant) and left (non-dominant) hands was also investigated. Eight subjects were scanned under four conditions. The first condition was preparing and executing the task by the right hand, and the second was preparing only. The third condition was preparing and executing the task by the left hand, and the fourth was resting as a control condition. The subjects were cued for preparation for grasp by a tape-recorded voice saying “prepare, ” which was followed by a beep at some interval (4-8 seconds). For the execute condition, the subjects grasped and lifted the object at the beep sound, while for the prepare-only condition, the subjects stopped the preparatory state. This was repeated 10 or 11 times during each PET scanning. For the prepare and execute condition, results were similar to the activated areas for lifting action in the first study. BA40, however, was activated in the left side this time. For the prepare-only condition, after subtracting the resting condition, left SMA and S1 were the activated areas, and for the execute-only condition (the prepare-execute condition minus the prepare-only condition), left M1 and thalamus, and right cerebellum hemisphere were activated. When the task was performed by the left hand, there was nearly a mirror image of the activated areas seen in the right-hand lifting condition. These findings provided fundamental data for understanding the neural network governing control of fingers in grip-lift-replacement actions.

Background. In hepatitis B virus- (HBV-) positive patients, the relationship between the metabolic variables and histological degree of liver fibrosis has been poorly investigated.Methods. A total of 176 HBV-positive patients were assessed in whom the ratios of glycated albumin-to-glycated hemoglobin (GA/HbA1c) were calculated in order to investigate the relationship with the degree of liver fibrosis.Results. The GA/HbA1c ratio increased in association with the severity of fibrosis (METAVIR scores: F0-1: 2.61 ± 0.24, F2: 2.65 ± 0.24, F3: 2.74 ± 0.38, and F4: 2.91 ± 0.63). The GA/HbA1c ratios were inversely correlated with four variables of liver function: the prothrombin time (PT) percentage (P<0.0001), platelet count (P<0.0001), albumin value (P<0.0001), and cholinesterase value (P<0.0001). The GA/HbA1c ratio was positively correlated with two well-known markers of liver fibrosis, FIB-4 (P<0.0001) and the AST-to-platelet ratio index (APRI) (P<0.0001). Furthermore, the GA/HbA1c showed better correlations with two variables of liver function (PT percentage and cholinesterase value) than did FIB-4 and with all four variables than did the APRI.Conclusion. The GA/HbA1c ratio is associated with the degree of liver fibrosis in HBV-positive patients.Corrigendum to “An Increased Ratio of Glycated Albumin to HbA1c Is Associated with the Degree of Liver Fibrosis in Hepatitis B Virus-Positive Patients”

Endothelin (ET) 1, a 21 amino acid constrictor peptide, is one of the most potent agonists of airway smooth muscle and acts on two different receptors, i.e., ETA and ETB receptors. Recently, it has been shown that there are species and organ differences in physiological roles of each ET receptor. In rats, however, the physiological roles of ET receptors remain to be clarified. We questioned whether ET-1 might affect airway and lung tissue via different ET receptor subtypes in rats. To answer this question, we investigated the effects of ET-1 on lung behaviour in anesthetized, open-chested, mechanically ventilated (f = 1 Hz, VT = 9 mL/kg, PEEP = 3 cmH2O (1 cmH2O = 98.1 Pa)) rats in the absence or the presence of ETA and ETB selective antagonists, i.e., BQ-123 and BQ-788, respectively. Using alveolar capsules, we calculated lung elastance (EL), resistance of lung (RL), tissue (Rti), and airway (Raw), and hysteresivity (eta = 2 pifRti/EL) under control conditions and after intravenous administration of ET-1 (10(-8) mol/kg). ET-1 induced significant increases in RL, Rti, Raw, EL, and eta. BQ-123 did not affect ET-1 induced constriction, while BQ-788 significantly reduced delta RL, delta Rti, delta Raw, delta EL during ET-1 induced constriction. The effects of the combination of BQ-123 and BQ-788 were not different compared with BQ-788. Eta was not affected by BQ-123 and BQ-788. These data suggest that ETB, but not ETA, receptors may have significant physiological roles in rat lungs in response to ET-1.

Nagase, Takahide, Tomoko Aoki, Teruaki Oka, Yoshinosuke Fukuchi, and Yasuyoshi Ouchi. ET-1-induced bronchoconstriction is mediated via ETB receptor in mice. J. Appl. Physiol. 83(1): 46–51, 1997.—Endothelin (ET)-1 is one of the most potent agonists of airway smooth muscle and can act via two different ET receptor subtypes, i.e., ETA and ETB. To determine the effects of ET-1 on in vivo pulmonary function and which ET receptors are involved in murine lungs, we investigated 1) the effects of ET and sarafotoxin S6c (S6c), a selective ETB agonist, on pulmonary function and 2) the effects of BQ-123 and BQ-788, specific ETA- and ETB-receptor antagonists, on ET-1-induced bronchoconstriction. ICR mice were anesthetized and mechanically ventilated (frequency = 2.5 Hz, tidal volume = 8 ml/kg, positive end-expiratory pressure = 3 cmH2O). Intravenous ET-1, ET-2, and ET-3 increased lung resistance similarly and equipotently, whereas S6c elicited a greater degree of bronchoconstriction. Mice were then pretreated with saline (Sal), BQ-123 (0.2, 1, and 5 mg/kg), or BQ-788 (0.2, 1, and 5 mg/kg) before administration of ET-1 (10−7 mol/kg iv). No dose of BQ-123 blocked ET-1-induced constriction, whereas pretreatment with each dose of BQ-788 significantly inhibited ET-1-induced responses. There were significant differences in morphometrically assessed airway constriction between Sal and BQ-788 and between BQ-123 and BQ-788, whereas no significant difference was observed between Sal and BQ-123. There were no significant morphometric differences in the airway wall area among the three groups. These observations suggest that the ETB- but not ETA-receptor subtype may mediate the changes in murine pulmonary function in response to ET-1. In addition, the ETB-receptor antagonist reduces ET-1-induced airway narrowing by affecting airway smooth muscle contraction in mice.

Hypersecretion of prolactin (PRL) has been implicated as one of the factors that mediate ethanol-induced hypogonadism, but the site(s) is the central nervous system where ethanol acts to lead to the stimulation of PRL secretion is unknown. To clarify the site(s) of ethanol action, medial basal hypothalamic deafferentation (MBHD) or medial basal hypothalamic ablation (MBHA) were performed stereotaxically in male rats, and their PRL secretory capacity in response to acute ethanol administration was compared with that of intact or sham-operated controls. In intact control rats, plasma immunoreactive PRL concentration increased markedly (P < .001 v saline injection) following ethanol 400 to 500 mg/100 g body weight (BW) intraperitoneally (IP). The PRL response was dose-related and reached a maximum plateau level at 15 minutes. Plasma PRL returned to a near-basal level by 60 minutes. The response was blocked completely (P < .001) by pretreatment with dopamine (1 mg per rat), a specific inhibitor of adenohypophyseal PRL secretion. In sham-operated rats and in MBHD and MBHA rats, ethanol (500 mg/100 g BW IP) induced a significant (P < .001 to .05) elevation of PRL relative to the respective saline treatment. The basal level was significantly (P < .005) lower in the MBHD group (5.3 ± 0.9 ng/mL) and significantly (P < .001) higher in the MBHA group (101.1 ± 15.7 ng/mL) than in the sham group (17.2 ± 5.9 ng/mL). These results suggest the following: (1) acute ethanol administration stimulates PRL secretion from the pituitary in a dose-related manner, (2) ethanol appears to have direct stimulatory effects on adenohypophyseal PRL secretion, and (3) extrahypothalamic brain areas exert a stimulatory influence and the hypothalamus an inhibitory influence on basal PRL secretion.

Hypothalamic growth hormone-releasing factor (GRF) in higher mammals, including human GRF, is a 44 amino acid residue peptide and is highly homologous in structure. By contrast, mouse GRF (mGRF) recently deduced by cDNA cloning consists of only 42 residues and shows relatively low homology to the GRFs of higher mammals and the same rodent species, rat. To characterize and localize the predicted mature mGRF peptide in the hypothalamus, we have generated its antiserum and developed a homologous radioimmunoassay. Immunoreactive mGRF in the acid hypothalamic extract was eluted as a single peak at a position identical to that of synthetic peptide on both gel filtration chromatography and reverse-phase high-performance liquid chromatography (HPLC). Secretion of immunoreactive mGRF from incubated hypothalami increased several fold in response to 50 mM K+, and this rise was abolished in the absence of medium Ca2+. Only a single peak of immunoreactive mGRF that coeluted with synthetic replicate was observed after the K+ -stimulated medium was extracted on Bond Elut C18 cartridges and applied on reverse-phase HPLC. Immunohistochemistry identified many mGRF-positive cell bodies in the arcuate nucleus and dense bundles of immunoreactive fibers in the median eminence. Treatment of mice with gold thioglucose (GTG), a chemical agent known to cause hypothalamic lesions, markedly depleted both content and in vitro secretion of immunoreactive mGRF. The decline in mGRF secretion was greater in GTG obese than in nonobese mice, whereas somatostatin secretion was not affected by GTG treatment. As compared to the previous findings obtained on rat GRF, mouse had approximately the same content of hypothalamic GRF, but retained only one third the capacity to release GRF in response to the same depolarizing stimulus. These findings demonstrate that mouse hypothalamus contains and secretes a mGRF-like molecule which has immunological and chromatographic characteristics identical to that predicted by molecular cloning. The depolarization-evoked, Ca2+-dependent release of immunoreactive mGRF and its neuronal localization in the arcuate nucleus-median eminence region indicate that it functions as a hypophysiotropic hormone of physiological importance. GTG produces hypothalamic GRF deficiency, probably sparing hypophysiotropic somatostatin neurons, and could be used to generate a mouse model for human GRF-deficient dwarfism.

The present study addressed the effect of loudness and tempo on kinematics and muscular activities of the upper extremity during repetitive piano keystrokes. Eighteen pianists with professional music education struck two keys simultaneously and repetitively with a combination of four loudness levels and four tempi. The results demonstrated a significant interaction effect of loudness and tempo on peak angular velocity for the shoulder, elbow, wrist and finger joints, mean muscular activity for the corresponding flexors and extensors, and their co-activation level. The interaction effect indicated greater increases with tempo when eliciting louder tones for all joints and muscles except for the elbow velocity showing a greater decrease with tempo. Multiple-regression analysis and K-means clustering further revealed that 18 pianists were categorized into three clusters with different interaction effects on joint kinematics. These clusters were characterized by either an elbow-velocity decrease and a finger-velocity increase, a finger-velocity decrease with increases in shoulder and wrist velocities, or a large elbow-velocity decrease with a shoulder-velocity increase when increasing both loudness and tempo. Furthermore, the muscular load considerably differed across the clusters. These findings provide information to determine muscles with the greatest potential risk of playing-related disorders based on movement characteristics of individual pianists.

Both thyroid hormone and hypothalamic growth hormone (GH)-releasing factor (GRF) facilitate pituitary somatotroph function. However, the pathophysiological role of thyroid hormone in GRF secretion is less well understood. Thyrotoxicosis, induced by administration of thyroxine (T4) in rats, inhibited both pituitary GH levels and immunoreactive GRF secretion from incubated hypothalamus. At the highest dose of T4 given for 12 d, GRF secretion and pituitary GH decreased by 50 and 39%, respectively. Hypothyroidism induced by thyroidectomy (Tx) enhanced GRF secretion approximately twofold while depleting pituitary GH by greater than 99%. Both of these hypothalamic and pituitary effects were reversed by replacement of T4 but not human GH for 7 or 14 d. Human GH was as potent as T4 in restoring decreased body weight gains or serum insulin-like growth factor-1 levels in Tx rats. These results indicate that at both physiological and pathological concentrations in serum, thyroid hormone acts as an inhibitory modulator of GRF secretion, probably not involving a feedback mechanism through GH. A biphasic effect of thyroid hormone on pituitary GH levels appears to derive from the difference in primary target tissues of hyper- and hypothyroidism, the hypothalamus and the pituitary, respectively.

Introduction As a component of midwife care, eliminating clothing that constricts the trunk has been shown to markedly elevate the uterine fundus, soften the uterus and abdomen, and reduce the abdominal wall tension in women admitted to hospital due to the risk of miscarriage or premature delivery. However, no prospective study has conclusively verified the efficacy of avoiding constrictive clothes around the trunk in pregnant women. We aim to verify the efficacy of instructing pregnant women to wear loose clothing that does not constrict the trunk to reduce the risk of premature birth and improve quality of life (QoL) during pregnancy. Methods and analysis We will conduct a randomised controlled trial of pregnant women scheduled to deliver at the National Center for Child Health and Development in Tokyo, Japan. A total of 616 pregnant women, from whom written informed consent will be obtained, will be allocated randomly to an intervention group or a control group. Women in the control group will be provided with anaemia prevention leaflets at 20 weeks’ gestation and skin-care leaflets at 30 weeks’ gestation. Women in the intervention group will be provided with the same leaflets and will also receive health advice from health professionals to avoid constrictive clothing around the trunk. The primary outcome will be a difference between these groups in the frequency of any one of the following category variables: (1) cervical length Ethics and dissemination The Institutional Review Board and Ethics Committee at the National Center for Child Health and Development, Japan, has approved this study. Our findings will be widely disseminated through conference presentations and peer-reviewed publications. Trial registration number UMIN000016853.

Using positron emission tomography (PET), the brain regions recruited for the tapping movement by different fingers and different tapping modes were investigated in ten young healthy volunteers without specific finger training. Auditory-paced (2 Hz) tapping movements were performed by the index (I) or ring (R) finger alone (single-finger tapping) and by the alternate use of the I and middle (M) fingers or the R and little (L) fingers (double-finger tapping). Each subject also provided subjective rankings of perceived task difficulty, as well as muscular fatigue, among the tapping tasks. The activated areas of the brain during tapping by the R finger were more extensive in the frontal and temporal areas, as well as the cerebellum, than during tapping by the I finger. A similar result was revealed for the comparison of the RL and IM finger pairs. The perceived task difficulty, as well as muscular fatigue, was also higher for the R finger or RL finger pair than the I finger or IM finger pair. These results indicate that movement of individual fingers or finger pairs with different levels of task difficulty is represented differently in the structures of cortical and subcortical systems. A comparison of the single- and double-finger modes revealed that in addition to the brain areas activated during single-finger mode, the bilateral dorsal premotor and left primary motor/sensory areas and the right anterior cerebellum were also activated during the double-finger mode. These additional areas could be essential structures for the execution and motor sequence operation of the two fingers.

Using 12 healthy male subjects, the dynamic motor ability of individual fingers was investigated under four different finger tapping conditions. These were: maximum speed tapping with one finger (single-finger tapping), alternate movement of two fingers (double-finger tapping), double-finger tapping in an unsupported condition, and submaximum constant speed tapping with one finger in a passive manner. Key-contact forces for all fingers and the movement velocity of the tapping finger were monitored. With the exception of the unsupported condition, non-tapping fingers were maintained in contact with designated keys during the tapping tasks. It was found that the index finger attained the fastest cadence and greatest movement velocity, followed by the middle, little and ring fingers, respectively. Subjective assessment of rank order of "difficulty" of tapping by the subjects was highly correlated with tapping cadence. Thus dynamic motor function, as indicated by rapid, repetitive movement, differs among the individual fingers. Parallel changes were observed in the key-contact force of the neighboring non-tapping fingers during tapping. The range of the non-tapping finger forces was largest during tapping by the ring finger. A similar trend was found for passive tapping, during which the magnitude of key-contact force was less than one-third of that observed during active tapping. The lower cadence achieved by the ring finger may be attributed more to a lack of independence at the level of voluntary neuromuscular control, than to innate mechanical interaction with the other fingers. Tapping cadence of each finger was lower for the double-finger mode than for the single-finger mode. The magnitude of the observed decrease in cadence during double-finger tapping was, on the other hand, strongly dependent on finger-combination. The decrease was smallest for the index-middle finger-combination, and greatest for the ring-little finger-combination. Compatibilities with other fingers can play an essential role in the dynamic motor function of individual fingers. During the unsupported task, in which interactions were diminished by allowing all fingers to move freely, tapping cadence increased markedly. Therefore, the lower cadences observed in specific finger-combinations may be partly attributed to anatomical and neural interdigit interactions.

Bronchial hyperresponsiveness and eosinophilia are major characteristics of asthma. Calcitonin gene-related peptide (CGRP) is a neuropeptide that has various biological actions. In the present study, we questioned whether CGRP might have pathophysiological roles in airway hyperresponsiveness and eosinophilia in asthma. To determine the exact roles of endogenous CGRP in vivo, we chose to study antigen-induced airway responses using CGRP gene-disrupted mice. After ovalbumin sensitization and antigen challenge, we assessed airway responsiveness and measured proinflammatory mediators. In the sensitized CGRP gene-disrupted mice, antigen-induced bronchial hyperresponsiveness was significantly attenuated compared with the sensitized wild-type mice. Antigen challenge induced eosinophil infiltration in bronchoalveolar lavage fluid, whereas no differences were observed between the wild-type and CGRP-mutant mice. Antigen-induced increases in cysteinyl leukotriene production in the lung were significantly reduced in the CGRP-disrupted mice. These findings suggest that CGRP could be involved in the antigen-induced airway hyperresponsiveness, but not eosinophil infiltration, in mice. The CGRP-mutant mice may provide appropriate models to study molecular mechanisms underlying CGRP-related diseases.

We report a Japanese family carrying a T666M missense mutation of CACNA1A. Affected members demonstrated a strikingly wide clinical spectrum including migraine, hemiplegia, coma, and progressive cerebellar ataxia. Despite such variability of the clinical features, they demonstrated similar magnetic resonance imaging findings demonstrating cerebellar atrophy predominantly of the cerebellar vermis. These magnetic resonance images appeared not to correlate with clinical severity. Our findings should indicate that a T666M mutation of CACNA1A may be associated with more variable clinical features and that paroxysmal hemiplegic migraine attacks and progressive cerebellar atrophy should have distinct mechanisms of pathogenesis.

症例は43歳,男性.発熱と前胸部の皮膚潰瘍を主訴として入院.血液学的検査にてMDSと診断し,蛋白同化ホルモン・副腎皮質ホルモンおよび抗生物質を投与したところ,血液学的所見・皮膚症状は改善した.その後も類似の皮膚の疼痛・発赤・潰瘍を繰り返した. PGと考えアザチオプリンを投与したところ症状は急速に改善した.本例は,発症に免疫学的機序が考えられているPGを合併した, MDSの興味深い症例と思われる.

Endothelin-1 (ET-1) has recently been reported to have a potential pathophysiologic role in bronchial asthma. In the current study, we hypothesized whether ET-1 and a gene encoding ET-1 might be involved in airway hyperresponsiveness (AHR), which is a major feature of bronchial asthma. To test this hypothesis, we investigated airway responsiveness in ET-1(+/-) heterozygous knockout mice, which genetically produce lower levels of ET-1, and in ET-1(+/+) wild-type mice. Airway responsiveness was assessed through the concentration of an agonist required to double lung resistance (EC200 RL). Unexpectedly, airway responsiveness to methacholine was markedly enhanced in ET-1(+/-) heterozygous mice as compared with ET-1(+/+) wild-type mice (EC200 RL: 1.8 +/- 0.1 versus 21.6 +/- 5.6 mg/ml, p0.002). Pretreatment with the nitric oxide (NO) synthase inhibitor Ng-monomethyl-L-arginine (L-NMMA) significantly enhanced methacholine responsiveness in ET-1(+/+) wild-type mice, but not in ET-1(+/-) heterozygous mice. Meanwhile, there was no difference between ET-1(+/-) heterozygous mice and the wild-type mice in airway responsiveness to 5-hydroxytryptamine (5-HT). In sensitized mice, no significant differences in responsiveness to antigen were observed between the two groups. These findings suggest that the gene encoding ET-1 may be potentially involved in the etiology of airway hyperreactivity, and that the decrease in ET-1 concentration is associated with AHR to methacholine. In mice, ET-1 as well as NO may have a significant role in the homeostasis of airway physiology.

Nagase, Takahide, Hirotoshi Matsui, Tomoko Aoki, Yasuyoshi Ouchi, and Yoshinosuke Fukuchi. Lung tissue behavior in the mouse during constriction induced by methacholine and endothelin-1. J. Appl. Physiol. 81(6): 2373–2378, 1996.—Recently, mice have been extensively used to investigate the pathogenesis of pulmonary disease because appropriate murine models, including transgenic mice, are being increasingly developed. However, little information about the lung mechanics of mice is currently available. We questioned whether lung tissue behavior and the coupling between dissipative and elastic processes, hysteresivity (η), in mice would be different from those in the other species. To address this question, we investigated whether tissue resistance (Rti) and η in mice would be affected by varying lung volume, constriction induced by methacholine (MCh) and endothelin-1 (ET-1), and high-lung-volume challenge during induced constriction. From measured tracheal flow and tracheal and alveolar pressures in open-chest ICR mice during mechanical ventilation [tidal volume = 8 ml/kg, frequency (f) = 2.5 Hz], we calculated lung resistance (Rl), Rti, airway resistance (Raw), lung elastance (El), and η (= 2πfRti/El). Under baseline conditions, increasing levels of end-expiratory transpulmonary pressure decreased Raw and increased Rti. The administration of aerosolized MCh and intravenous ET-1 increased Rl, Rti, Raw, and El in a dose-dependent manner. Rti increased from 0.207 ± 0.010 to 0.570 ± 0.058 cmH2O ⋅ ml−1 ⋅ s after 10−7 mol/kg ET-1 ( P < 0.01). After induced constriction, increasing end-expiratory transpulmonary pressure decreased Raw. However, η was not affected by changing lung volume, constriction induced by MCh and ET-1, or high-lung-volume challenge during induced constriction. These observations suggest that 1) η is stable in mice regardless of various conditions, 2) Rti is an important fraction of Rl and increases after induced constriction, and 3) mechanical interdependence may affect airway smooth muscle shortening in this species. In mammalian species, including mice, analysis of η may indicate that both Rti and El essentially respond to a similar degree.

It has been reported that hyperpnea-induced bronchoconstriction in guinea pigs is a potential model for exercise-induced asthma in humans. We hypothesized that calcitonin gene-related peptide (CGRP) could modulate leukotriene D4 (LTD4)-induced responses and be involved in the pathophysiology in this asthma model. We measured tracheal (Ptr) and alveolar pressure (PA) using alveolar capsules in open-chested, mechanically ventilated (f = 1 Hz, VT = 9 ml/kg, PEEP = 4 cm H2O) guinea pigs. Animals were intravenously pretreated with saline (SAL), CGRP(8-37) (CGRP receptor antagonist), CGRP, MK-571 (LTD4 receptor antagonist), MK-886 (5-lipoxygenase inhibitor), or CGRP(8-37) + MK-571, and then underwent dry gas hyperpnea challenge (HC, 95% 02-5% CO2, 150 breaths/min, 7 min). We calculated resistance of lung (RL), tissue (Rti), and airway (Raw). HC increased RL, Rti, and Raw in SAL controls (322 +/- 27, 430 +/- 59, 299 +/- 23% baseline, respectively). MK-571, MK-886, and CGRP significantly reduced the responses to HC, while CGRP(8-37) enhanced HC-induced responses. Pretreatment with CGRP(8-37) and MK-571 in combination attenuated HC-induced constriction. In addition, pretreatment with CGRP reduced responses induced by intravenous administration of LTD4. These observations suggest that CGRP might be involved in the pathophysiology of hyperpnea-induced constriction in guinea pigs via modulation of LTD4-elicited responses.

Infections in elderly bed-bound nursing home patients are serious care problems. In order to protect against infections we adopted bactericidal clothes (Sanmo Co., Kyoto, Japan). First, we studied how bactericidal clothes sterilise bacteria in vitro. The bactericidal clothes kill methicillin-resistant Staphylococcus aureus (MRSA), E. Coli, Krebsiella and Pseudomonas aureus , over 99%, 3 h after contact, while these bacteria can survive over 18 h on conventional cotton clothes. Second, ninety elderly patients were divided into two groups; the control group and the “treated” group with bactericidal clothes. In Period 1 neither group received particular treatment for three months and in Period 2 only the treated group used bactericidal clothes for three months. The control group in Period 2 used regular clothes throughout. The number of febrile days was significantly lower for the treated group, compared with the control group. It is suggested that the bactericidal clothes reduce infections in elderly patients.