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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.

Immune checkpoint inhibitors (ICIs) targeting programmed cell death 1 (PD-1) and cytotoxic T-lymphocyte antigen-4 (CTLA-4) are widely used to treat advanced metastatic cancers. Neutralisation of PD-1 or CTLA-4 by ICIs results in immune-related adverse events (irAEs). The clinicopathological features of twelve patients with hepatic irAEs were evaluated and compared to those of ten patients with autoimmune hepatitis (AIH) or graft-versus-host disease (GVHD). No significant difference was seen in serum levels of transaminases, whereas serum levels of IgG and anti-nuclear antibody were higher in patients with AIH than in those with GVHD or hepatic irAEs. Inflammation was limited to the liver lobes in patients with GVHD or hepatic irAEs, whereas patients with AIH exhibited both portal and lobular inflammation. Immunohistochemical analyses revealed a predominant infiltration of CD8+ T cells and defective accumulation of regulatory T cells (Tregs) expressing forkhead box p3 (FOXP3) in the lobular areas of patients with hepatic irAEs and GVHD. In contrast, periportal lesions of patients with AIH were characterised by an infiltration of CD4+ T cells, CD8+ T cells, CD20+ B cells, and FOXP3+ Tregs. Overall, the activation of CD8+ T cells in the absence of activation of Tregs potentially underlies the immunopathogenesis of hepatic irAEs.

The incidence of hepatocellular carcinoma (HCC) related to non-alcoholic fatty liver disease (NAFLD) is increasing worldwide. We analyzed 16 surgically resected HCC cases in which the background liver was pathologically diagnosed as NAFLD. Specimens with Brunt classification grade 3 or higher were assigned as the fibrotic progression group (n = 8), and those with grade 1 or lower were classified as the non-fibrosis progression group (n = 8). Comprehensive mutational and methylome analysis was performed in cancerous and noncancerous tissues. The target gene mutation analysis with deep sequencing revealed that CTNNB1 and TP53 mutation was observed in 37.5% and TERT promoter mutation was detected in 50% of cancerous samples. Furthermore, somatic mutations in non-cancerous samples were less frequent, but were observed regardless of the progression of fibrosis. Similarly, on cluster analysis of methylome data, status for methylation events involving non-cancerous liver was similar regardless of the progression of fibrosis. It was found that, even in cases of non-progressive fibrosis, accumulation of gene mutations and abnormal methylation within non-cancerous areas were observed. Patients with NAFLD require a rigorous liver cancer surveillance due to the high risk of HCC emergence based on the accumulation of genetic and epigenetic abnormalities, even when fibrosis is not advanced.

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

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.

We investigated the diagnostic capability of the proprietary attenuation imaging (ATI) modality found on some Canon Medical Systems Corp. ultrasound scanners to detect histologically diagnosed steatosis in 148 patients. ATI values increased significantly with increasing steatosis grade (p0.001). The diagnostic values (area under the receiver operating characteristic curve) of ATI for steatosis grades ≥ 1 (5%-33% of hepatocytes), ≥ 2 (33%-66% of hepatocytes) and 3 (66% of hepatocytes) were 0.85, 0.91 and 0.91. In addition, ATI values increased significantly with increasing steatosis grades (p = 0.002) even in obese patients (n = 41). The diagnostic values of ATI for steatosis grades ≥ 1, ≥ 2 and 3 in obese patients were 0.72, 0.72 and 0.78. Furthermore, ATI values increased significantly with increasing steatosis grade (p0.001) in patients with non-alcoholic fatty liver disease (NAFLD) (n = 38). The diagnostic values of ATI for steatosis grades ≥ 1, ≥ 2 and 3 in NAFLD patients were 0.77, 0.88 and 0.86. In conclusion, the ATI method showed good diagnostic capability for the detection of hepatic steatosis.

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.

Using PET, brain areas representing the use of a well‐learned tool (chopsticks) were investigated in 10 normal common users. The experimental task was to hold the tool in their right hand and use it to pick up and transport a small pin from a table. Data for the same task performed using only the fingers were also obtained as a control. The results showed an extensive overlap in activated areas with and without the use of the tool. The tool‐use prehension, compared to the finger prehension, was associated with higher activities in the caudal‐ventral premotor, dorsal premotor, superior parietal, posterior intraparietal, middle temporal gyrus, and primary sensory, occipital cortices, and the cerebellum. These are thus considered to be the human cortical and subcortical substrates representing the use of the tool studied. The activity of the posterior intraparietal area was negatively correlated with the number of drops of the pin, whereas occipital activity was positively correlated with the same error parameter. The caudal‐ventral premotor and posterior intraparietal areas are together known to be involved in tool use‐related modulation in peripersonal space. The correlation results suggest that this modulation depends on the level of performance. The coactivated left middle temporal gyrus further suggests that familiarity with a tool as well as the knowledge about its usage plays a role in peripersonal space modulation. Superior parietal activation, along with occipital activation, indicates the involvement of visual‐spatial attention in the tool use, possibly reflecting the effect of interaction between the prehension (task) and the tool. Hum Brain Mapp 2009. © 2009 Wiley‐Liss, Inc.

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.

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 effects of surface friction at the digit-object interface on digit forces were studied when subjects (n=8) statically held an object in a five-digit grasp. The friction conditions were SS (all surfaces are sandpaper), RR (all are rayon), SR (S for the thumb and R for the four fingers), and RS (the reverse of SR). The interaction effects of surface friction and external torque were also examined using five torques (–0.5, –0.25, 0, +0.25, +0.5 Nm). Forces and moments exerted by the digits on a handle were recorded. At zero torque conditions, in the SS and RR (symmetric) tasks the normal forces of the thumb and virtual finger (VF, an imagined finger with the mechanical effect equal to that of the four fingers) were larger for the RR than the SS conditions. In the SR and RS (asymmetric) tasks, the normal forces were between the RR and SS conditions. Tangential forces were smaller at the more slippery side than at the less slippery side. According to the mathematical optimization analysis decreasing the tangential forces at the more slippery sides decreases the cost function values. The difference between the thumb and VF tangential forces, ΔF t, generated a moment of the tangential forces (friction-induced moment). At non-zero torque conditions the friction-induced moment and the moment counterbalancing the external torque (equilibrium-necessitated moment) could be in same or in opposite directions. When the two moments were in the same direction, the contribution of the moment of tangential forces to the total moment was large, and the normal forces were relatively low. In contrast, when the two moments were in opposite directions, the contribution of the moment of tangential forces to the total moment markedly decreased, which was compensated by an increase in the moment of normal forces. The apparently complicated results were explained as the result of summation of the friction-related (elemental) and torque-related (synergy) components of the central commands to the individual digits.

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.

Acute respiratory distress syndrome (ARDS) is an acute lung injury of high mortality rate, and sepsis syndrome is one of the most frequent causes of ARDS. Metabolites of arachidonic acid, including thromboxanes and leukotrienes, are proinflammatory mediators and potentially involved in the development of ARDS. A key enzyme for the production of these inflammatory mediators is cytosolic phospholipase A2(cPLA2). Recently, it has been reported that arachidonyl trifluoromethyl ketone (ATK) is a potent inhibitor of cPLA2. In the present study, we hypothesized that pharmacological intervention of cPLA2could affect acute lung injury. To test this hypothesis, we examined the effects of ATK in a murine model of acute lung injury induced by septic syndrome. The treatment with ATK significantly attenuated lung injury, polymorphonuclear neutrophil sequestration, and deterioration of gas exchange caused by lipopolysaccharide and zymosan administration. The current observations suggest that pharmacological intervention of cPLA2could be a novel therapeutic approach to acute lung injury caused by sepsis syndrome.

The purposes of this study were: (1) to provide descriptive temporal and force data for fast alternate tapping by the index and middle fingers ('double-finger mode'), and to compare it with one finger fast tapping ('single-finger mode'); (2) to determine any differences in the dynamic motor function of individual fingers with these tapping tasks; and (3) to determine any differences between the single-finger mode and tapping with the whole hand ('hand mode'). Eleven healthy males tapped force transducer(s) for 7 s as fast as possible using their dominant hand. The double-finger mode had a greater peak force and a 50% faster tapping frequency than the single-finger mode. There was no correlation between the single-finger and double-finger modes in the temporal data. Tapping with two fingers thus seems to be organized with a motor strategy that is different from that with one finger, and can possibly capture an individual's additional or different motor function. A comparison between the two fingers revealed that the index finger had a significantly faster tapping frequency, indicating the superiority of the index finger over the middle finger in terms of dynamic motor function. The hand mode had a significantly faster tapping frequency with greater peak force than the single-finger mode. A distinction is essential between these two modes.

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.

The prevention of cyclophosphamide-induced urotoxicity by disulfiram was studied in mice. A single dose of cyclophosphamide (100-400 mg/kg, intraperitoneally) produced a significant dose-dependent increase in urinary bladder weight within 48 hr of treatment. Disulfiram prevented cyclophosphamide-induced bladder damage in a dose-dependent manner in mice when orally administered simultaneously with antitumour agents, but failed to diminish the acute toxicity, leukocytotoxicity and immunotoxicity of cyclophosphamide. The protective effect of disulfiram on the bladder was critically dependent on administration timing. Oral administration of disulfiram between 60 min. before and 60 min. after the injection of cyclophosphamide was found to be effective. The optimum time was simultaneous administration of both drugs. Diethyldithiocarbamate and carbon disulfide, metabolites of disulfiram, prevented cyclophosphamide-induced bladder damage when administered simultaneously with cyclophosphamide 1 to, 3 or 5 hr afterwards. Disulfiram slightly potentiated the antitumour activity of cyclophosphamide against Sarcoma 180 or EL-4 leukaemia in vivo when administered simultaneously with cyclophosphamide. In contrast, diethyldithiocarbamate or carbon disulfide did not interfere with cyclophosphamide antitumour activity when administered 3 hr after cyclophosphamide. From these preliminary studies, disulfiram appears to be a likely candidate for protection against cyclophosphamide-induced urotoxicity without compromising the therapeutic utility of the alkylating agent.

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.

The authors studied the effects of surface friction at the digit-object interface on digit forces and moments when 12 participants statically held an object in a 5-digit grasp. The authors changed low-friction contact (LFC) with rayon and high-friction contact (HFC) with sandpaper independently for each digit in all 32 possible combinations. Normal forces of the thumb and virtual finger (VF), an imagined finger with a mechanical effect equal to that of the 4 fingers, increased with the thumb at LFC or with an increase in the number of fingers at LFC. When the thumb was at LFC, the thumb tangential force decreased. The VF tangential force decreased when the number of fingers at LFC increased. The interaction of the local responses to friction and the synergic responses necessary to maintain the equilibrium explain the coordination of individual digit forces.

The relationship between the key depression force on an upright piano and the level of loudness of a generated tone was examined when pianists hit a force-sensor built-in key with "struck" or "pressed" type of touch. The vertical displacement of the key, and the radiated piano sounds were also recorded. It was found that for both types of touch, simple exponential functions could adequately describe the relation of the force amplitude with the level of the piano tone as well as that of the impulse of the force with the piano tone. The impulse of the force generated before the maximum key depression moment commonly amounted to above 80% of the total impulse produced at the tone below mezzo-forte. It, however, decreased to around 60% at fortissimo, indicating a decrease in the efficiency of the force application for sound production. The two types of touch differed in their force profiles. The struck touch was characterized by a steeper initial force increase with greater fluctuations in the subsequent period than the pressed touch. The struck touch also demonstrated lower maximum force and less impulse at fortissimo. The inter-pianist variation in the force and impulse, and the "finger-noise" are also herein examined.

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.

A 54-year-old man with a past history of gastric malignant lymphoma treated by the total gastrectomy and the chemotherapy, developed bilateral sudden deafness one year later. Two years after the gastrectomy he became abruptly paraplegic with sensory impairments of the lower extremities and neurogenic bladder. Serum LDH and soluble IL-2 receptor were high in titers (552 U/l and 1,090 U/l, normal range 145-519). Although the imaging studies of the spinal cord were negative, the myelopathic symptoms resolved dramatically after a course of pulse dose methylprednisolone therapy. However, he soon developed an abnormal behavior and mental deterioration in 3 weeks. The MRIs of the brain revealed abnormal signals compatible with multiple cerebral infarctions. As intravascular malignant lymphomatosis (IML) was suspected because of the laboratory and MRI findings, biopsies of the skin, the bone marrow, the muscle and the lymph node were carried out, without evidence of lymphoma. The brain biopsy ultimately confirmed the presence of IML. The patient remarkably responded to biweekly CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone) therapy in terms of regaining the mental alertness and improved hearing. However, the CHOP therapy was prematurely interrupted prior to completion because of infective arthritis. The relapse soon ensued, and he died 6 months after admission. This case was of interest because a solid gastric lymphoma appears to have transformed into the form of intravascular lymphomatosis without mass formations or leukemic changes. Although the neurological symptoms in association with IML are thought to be the results of ischemic events, this case illustrates a remarkable reversibility of the symptoms. This implies that the cerebral symptoms are not necessarily the results of typical ischemic infarction, but due to relative ischemia because of chiefly capillary-venous occlusion by lymphoma cells. The majority of the symptoms is thus attributable to the functional impairment. Therefore, the therapeutic intervention may dramatically improve the symptoms due to IML.

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.

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.