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Visuomotor adaptation is a form of motor learning that enables accurate limb movements in the presence of altered environmental or internal conditions. It requires updating the mapping between visual input and motor output, and can occur when learning a new device/tool or during rehabilitation after neurological injury. In either case, it is desirable to stabilize, or consolidate, this visuomotor memory for long-term usage. However, reactivation of a consolidated memory, whether it is motor-based or not, is thought to render it temporarily fragile again, and thus susceptible to interference or modification. Here, we determined if visuomotor memories demonstrate long-term retention but are fragile once reactivated. We used prism lenses to create a novel visuomotor mapping, which participants learned while having to walk and step to the center of targets. We re-tested this memory after one week and one year. We found that the mapping is retained for at least one year, regardless of whether participants were exposed to an interfering (i.e., opposing) mapping in the first session. We also found that presenting an opposing mapping in a block of trials following reactivation of the memory one year later did not disrupt subsequent performance when we re-tested the original memory. Our results suggest that these visuomotor memories are stored for extended periods of time and have limited fragility. Taken together, our results highlight the robustness of visuomotor memories associated with walking.

A CpG-stimulated autologous tumor cell vaccine for patients with MCL is safe and feasible and induces detectable antitumor T cell immune responses. Patients who received the CpG-MCL vaccination demonstrated freedom from MRD at 1 yr after ASCT that surpassed previously reported rates., Here, we report on the results of a phase I/II trial (NCT00490529) for patients with mantle cell lymphoma who, having achieved remission after immunochemotherapy, were vaccinated with irradiated, CpG-activated tumor cells. Subsequently, vaccine-primed lymphocytes were collected and reinfused after a standard autologous stem cell transplantation (ASCT). The primary endpoint was detection of minimal residual disease (MRD) within 1 yr after ASCT at the previously validated threshold of ≥1 malignant cell per 10,000 leukocyte equivalents. Of 45 evaluable patients, 40 (89%) were found to be MRD negative, and the MRD-positive patients experienced early subsequent relapse. The vaccination induced antitumor CD8 T cell immune responses in 40% of patients, and these were associated with favorable clinical outcomes. Patients with high tumor PD-L1 expression after in vitro exposure to CpG had inferior outcomes. Vaccination with CpG-stimulated autologous tumor cells followed by the adoptive transfer of vaccine-primed lymphocytes after ASCT is feasible and safe.

© 2020 Elsevier Inc. Learning a new motor task modifies feedforward (i.e., voluntary) motor commands and such learning also changes the sensitivity of feedback responses (i.e., reflexes) to mechanical perturbations [1–9]. For example, after people learn to generate straight reaching movements in the presence of an external force field or learn to reduce shoulder muscle activity when generating pure elbow movements with shoulder fixation, evoked stretch reflex responses to mechanical perturbations reflect the learning expressed during self-initiated reaching. Such a transfer from feedforward motor commands to feedback responses is thought to take place because of shared neural circuits at the level of the spinal cord, brainstem, and cerebral cortex [10–13]. The presence of shared neural resources also predicts the transfer from feedback responses to feedforward motor commands. Little is known about such a transfer presumably because it is relatively hard to elicit learning in reflexes without engaging associated voluntary responses following mechanical perturbations. Here, we demonstrate such transfer by leveraging two approaches to elicit stretch reflexes while minimizing engagement of voluntary motor responses in the learning process: applying very short mechanical perturbations [14–19] and instructing participants to not respond to them [20–26]. Taken together, our work shows that transfer between feedforward and feedback control is bidirectional, furthering the notion that these processes share common neural circuits that underlie motor learning and transfer.

As we walk, we must accurately place our feet to stabilize our motion and to navigate our environment. We must also achieve this accuracy despite imperfect sensory feedback and unexpected disturbances. In this study we tested whether the nervous system uses state estimation to beneficially combine sensory feedback with forward model predictions to compensate for these challenges. Specifically, subjects wore prism lenses during a visually guided walking task, and we used trial-by-trial variation in prism lenses to add uncertainty to visual feedback and induce a reweighting of this input. To expose altered weighting, we added a consistent prism shift that required subjects to adapt their estimate of the visuomotor mapping relationship between a perceived target location and the motor command necessary to step to that position. With added prism noise, subjects responded to the consistent prism shift with smaller initial foot placement error but took longer to adapt, compatible with our mathematical model of the walking task that leverages state estimation to compensate for noise. Much like when we perform voluntary and discrete movements with our arms, it appears our nervous systems uses state estimation during walking to accurately reach our foot to the ground. NEW & NOTEWORTHY Accurate foot placement is essential for safe walking. We used computational models and human walking experiments to test how our nervous system achieves this accuracy. We find that our control of foot placement beneficially combines sensory feedback with internal forward model predictions to accurately estimate the body's state. Our results match recent computational neuroscience findings for reaching movements, suggesting that state estimation is a general mechanism of human motor control.

Our understanding of how we learn and retain motor behaviors is still limited. For instance, there is conflicting evidence as to whether the memory of a learned visuomotor perturbation consolidates; i.e., the motor memory becomes resistant to interference from learning a competing perturbation over time. Here, we sought to determine the factors that influence consolidation during visually guided walking. Subjects learned a novel mapping relationship, created by prism lenses, between the perceived location of two targets and the motor commands necessary to direct the feet to their positions. Subjects relearned this mapping 1 wk later. Different groups experienced protocols with or without a competing mapping (and with and without washout trials), presented either on the same day as initial learning or before relearning on day 2. We tested identical protocols under constant and noisy mapping structures. In the latter, we varied, on a trial-by-trial basis, the strength of prism lenses around a non-zero mean. We found that a novel visuomotor mapping is retained at least 1 wk after initial learning. We also found reduced foot-placement error with relearning in constant and noisy mapping groups, despite learning a competing mapping beforehand, and with the exception of one protocol, with and without washout trials. Exposure to noisy mappings led to similar performance on relearning compared with the equivalent constant mapping groups for most protocols. Overall, our results support the idea of motor memory consolidation during visually guided walking and suggest that constant and noisy practices are effective for motor learning. NEW & NOTEWORTHY The adaptation of movement is essential for many daily activities. To interact with targets, this often requires learning the mapping to produce appropriate motor commands based on visual input. Here, we show that a novel visuomotor mapping is retained 1 wk after initial learning in a visually guided walking task. Furthermore, we find that this motor memory consolidates (i.e., becomes more resistant to interference from learning a competing mapping) when learning in constant and noisy mapping environments.

Humans have the remarkable ability to hold, grasp, and manipulate objects. Previous work has reported rapid and coordinated reactions in hand and shoulder muscles in response to external perturbations to the arm during object manipulation; however, little is known about how somatosensory feedback of an object slipping in the hand influences responses of the arm. We built a hand-held device to stimulate the sensation of slipping at all five fingertips. The device was integrated into an exoskeleton robot that supported it against gravity. The setup allowed us to decouple somatosensory stimulation in the fingers from forces applied to the arm— two variables that are highly interdependent in real-world scenarios. Fourteen participants performed three experiments in which we measured their arm feedback responses during slip stimulation. Slip stimulations were applied horizontally, in one of two directions, and participants were either instructed to follow the slip direction, or to move the arm in the opposite direction. Participants showed responses within ∼67 ms of slip onset when following the direction of slip, but significantly slower responses when instructed to move in the opposite direction. Arm responses were modulated by the speed but not the distance of the slip. Finally, when slip stimulation was combined with mechanical perturbations to the arm, we found that sensory information from the fingertips significantly modulated the shoulder feedback response. Overall, the results demonstrate the existence of a rapid feedback system that stabilizes hand-held objects.NEW & NOTHEWORTHYWe tested whether the sensation of an object slipping from the fingers modulates shoulder feedback responses. We found rapid shoulder feedback responses when participants were instructed to follow the slip direction with the arm. Shoulder responses following mechanical joint perturbations were also potentiated when combined with slipping. These results demonstrate the existence of fast and automatic feedback responses in the arm in reaction to sensory input to the fingertips that maintain grip on hand-held objects.

A common goal of motor learning is generalizing newly learned movement patterns beyond the training context. Here we tested whether learning a new physical property of the arm during self-initiated reaching generalizes to new arm configurations. One hundred human participants performed a single-joint elbow reaching task and/or countered mechanical perturbations that created pure elbow motion. Participants did so with the shoulder joint either free to rotate or locked by the robotic manipulandum. With the shoulder free, we found activation of shoulder extensor muscles for pure elbow extension trials, as required to counter the interaction torques that arise at the shoulder due to forearm rotation. After locking the shoulder joint, we found a substantial reduction in shoulder muscle activity that developed slowly over many trials. This reduction is appropriate because locking the shoulder joint cancels the interaction torques that arise at the shoulder to do forearm rotation and thus removes the need to activate shoulder muscles. In our first three experiments, we tested whether this reduction generalizes when reaching is self-initiated in (1) a different initial shoulder orientation, (2) a different initial elbow orientation and (3) for a different reach distance/speed. We found reliable generalization across initial shoulder orientation and reach distance/speed but not for initial elbow orientation. In our fourth experiment, we tested whether generalization is also transferred to feedback control by applying mechanical perturbations and observing reflex responses in a distinct shoulder orientation. We found robust transfer to feedback control.New & NoteworthyHere we show that learning to reduce shoulder muscles activity following shoulder fixation generalizes to other movement conditions but does not generalize globally, indicating that the nervous system does not implement such learning by modifying a general internal model of arm dynamics.DisclosuresThe authors declare no conflict of interest.

Humans have a remarkable capacity to learn novel movement patterns in a wide variety of contexts. Recent work has shown that, when countering external forces, the nervous system adjusts not only voluntary (ie. feedforward) control but also reflex (ie. feedback) responses. Here we show that directly altering the physical properties of the arm (i.e. intersegmental dynamics) causes the nervous system to adjust feedforward control and that this learning also transfers to feedback responses even though they were never directly trained. In our first experiment, we altered intersegmental dynamics by asking participants to generate pure elbow movements with the shoulder joint either free to rotate or locked. Locking the shoulder joint cancels the interaction forces that arise at the shoulder during forearm rotation and thus removes the need to activate shoulder muscles to prevent shoulder joint rotation. We first asked whether the nervous system learns this altered mapping of intersegmental dynamics. In the baseline phase, we found robust activation of shoulder flexor muscles for pure elbow flexion trials prior to movement onset – as required to counter the intersegmental dynamics. After locking the shoulder joint in the adaptation phase, we found a substantial reduction in shoulder muscle activity over many trials. After unlocking the shoulder joint in the post-adaptation phase, we observed after-effects, as participants made systematic hand path errors. In our second experiment, we investigated whether such learning transfers to feedback control. Mechanical perturbations applied to the limb in the baseline phase revealed that feedback responses, like feedforward control, also appropriately countered intersegmental dynamics. In the adaptation phase, we found a substantial reduction in shoulder feedback responses – as appropriate for the altered intersegmental dynamics. We also found that this decay in shoulder feedback responses correlated across subjects with the amount of decay during feedforward control. Our work adds to the growing evidence that feedforward and feedback control share an internal model of the arm’s dynamics.

Purpose Outcomes for patients with diffuse large B-cell lymphoma remain heterogeneous, with existing methods failing to consistently predict treatment failure. We examined the additional prognostic value of circulating tumor DNA (ctDNA) before and during therapy for predicting patient outcomes. Patients and Methods We studied the dynamics of ctDNA from 217 patients treated at six centers, using a training and validation framework. We densely characterized early ctDNA dynamics during therapy using cancer personalized profiling by deep sequencing to define response-associated thresholds within a discovery set. These thresholds were assessed in two independent validation sets. Finally, we assessed the prognostic value of ctDNA in the context of established risk factors, including the International Prognostic Index and interim positron emission tomography/computed tomography scans. Results Before therapy, ctDNA was detectable in 98% of patients; pretreatment levels were prognostic in both front-line and salvage settings. In the discovery set, ctDNA levels changed rapidly, with a 2-log decrease after one cycle (early molecular response [EMR]) and a 2.5-log decrease after two cycles (major molecular response [MMR]) stratifying outcomes. In the first validation set, patients receiving front-line therapy achieving EMR or MMR had superior outcomes at 24 months (EMR: EFS, 83% v 50%; P = .0015; MMR: EFS, 82% v 46%; P < .001). EMR also predicted superior 24-month outcomes in patients receiving salvage therapy in the first validation set (EFS, 100% v 13%; P = .011). The prognostic value of EMR and MMR was further confirmed in the second validation set. In multivariable analyses including International Prognostic Index and interim positron emission tomography/computed tomography scans across both cohorts, molecular response was independently prognostic of outcomes, including event-free and overall survival. Conclusion Pretreatment ctDNA levels and molecular responses are independently prognostic of outcomes in aggressive lymphomas. These risk factors could potentially guide future personalized risk-directed approaches.

Moving the arm is complicated by mechanical interactions that arise between limb segments. Such intersegmental dynamics cause torques applied at one joint to produce movement at multiple joints and, in turn, the only way to create single joint movement is by applying torques at multiple joints. Here, we investigated whether the nervous system accounts for intersegmental limb dynamics across the shoulder, elbow, and wrist joints during self-initiated reaching and when countering external mechanical perturbations. Our first experiment tested whether the timing and amplitude of shoulder muscle activity accounts for interaction torques produced during single-joint elbow movements from different elbow initial orientations and over a range of movement speeds. We found that shoulder muscle activity reliably preceded movement onset and elbow agonist activity, and was scaled to compensate for the magnitude of interaction torques arising because of forearm rotation. Our second experiment tested whether elbow muscles compensate for interaction torques introduced by single-joint wrist movements. We found that elbow muscle activity preceded movement onset and wrist agonist muscle activity, and thus the nervous system predicted interaction torques arising because of hand rotation. Our third and fourth experiments tested whether shoulder muscles compensate for interaction torques introduced by different hand orientations during self-initiated elbow movements and when countering mechanical perturbations that caused pure elbow motion. We found that the nervous system predicted the amplitude and direction of interaction torques, appropriately scaling the amplitude of shoulder muscle activity during self-initiated elbow movements and rapid feedback control. Taken together, our results demonstrate that the nervous system robustly accounts for intersegmental dynamics, and that the process is similar across the proximal to distal musculature of the arm as well as between feedforward (i.e., self-initiated) and feedback (i.e., reflexive) control.NEW & NOTEWORTHYIntersegmental dynamics complicate the mapping between applied joint torques and the resulting joint motions. Here, we provide evidence that the nervous system robustly predicts these intersegmental limb dynamics across the shoulder, elbow and wrist joints during reaching and when countering external perturbations.

Previous studies have suggested that ID influences the depth of general anaesthesia (GA) and delays emergence from GA. In this retrospective cohort study, we investigated whether ID affects the time taken to emerge from GA.We selected dental patients who underwent GA at the Department of Dental Anaesthesiology, Okayama University Hospital, using predefined inclusion and exclusion criteria, before dividing the selected participants into ID and non-ID (control) groups. Relevant data were collected from electronic anaesthesia records. Emergence time, the time from the discontinuation of propofol and remifentanil to tracheal extubation, was recorded for each patient. We compared the data of the ID group and control group. The association between ID and the emergence time was tested for statistical significance. Multivariate linear regression analysis was used to control for confounders.A total of 97 cases (control = 50, ID = 47) were included in the study. The emergence time was significantly longer in the ID group (ID group: 15.8 ± 6.6 min, control group: 10.8 ± 3.6 min). The ID group included more men and lower propofol and remifentanil infusion rates. The treatment time was longer, and the mean bispectral index was lower in the ID group. Sevoflurane inhalation was used only for anaesthesia induction in the ID group. In the multivariate linear regression analysis, ID was found to be significantly associated with a longer emergence time.Our results suggest that ID is associated with a longer emergence time from GA.

Patients with diffuse large B cell lymphoma (DLBCL) exhibit marked diversity in tumor behavior and outcomes, yet the identification of poor-risk groups remains challenging. In addition, the biology underlying these differences is incompletely understood. We hypothesized that characterization of mutational heterogeneity and genomic evolution using circulating tumor DNA (ctDNA) profiling could reveal molecular determinants of adverse outcomes. To address this hypothesis, we applied cancer personalized profiling by deep sequencing (CAPP-Seq) analysis to tumor biopsies and cell-free DNA samples from 92 lymphoma patients and 24 healthy subjects. At diagnosis, the amount of ctDNA was found to strongly correlate with clinical indices and was independently predictive of patient outcomes. We demonstrate that ctDNA genotyping can classify transcriptionally defined tumor subtypes, including DLBCL cell of origin, directly from plasma. By simultaneously tracking multiple somatic mutations in ctDNA, our approach outperformed immunoglobulin sequencing and radiographic imaging for the detection of minimal residual disease and facilitated noninvasive identification of emergent resistance mutations to targeted therapies. In addition, we identified distinct patterns of clonal evolution distinguishing indolent follicular lymphomas from those that transformed into DLBCL, allowing for potential noninvasive prediction of histological transformation. Collectively, our results demonstrate that ctDNA analysis reveals biological factors that underlie lymphoma clinical outcomes and could facilitate individualized therapy.

Primary mediastinal B-cell lymphoma is a distinct subtype of diffuse large-B-cell lymphoma that is closely related to nodular sclerosing Hodgkin's lymphoma. Patients are usually young and present with large mediastinal masses. There is no standard treatment, but the inadequacy of immunochemotherapy alone has resulted in routine consolidation with mediastinal radiotherapy, which has potentially serious late effects. We aimed to develop a strategy that improves the rate of cure and obviates the need for radiotherapy.We conducted a single-group, phase 2, prospective study of infusional dose-adjusted etoposide, doxorubicin, and cyclophosphamide with vincristine, prednisone, and rituximab (DA-EPOCH-R) and filgrastim without radiotherapy in 51 patients with untreated primary mediastinal B-cell lymphoma. We used results from a retrospective study of DA-EPOCH-R from another center to independently verify the outcomes.The patients had a median age of 30 years (range, 19 to 52) and a median tumor diameter of 11 cm; 59% were women. During a median of 5 years of follow-up, the event-free survival rate was 93%, and the overall survival rate was 97%. Among the 16 patients who were involved in the retrospective analysis at another center, over a median of 3 years of follow-up, the event-free survival rate was 100%, and no patients received radiotherapy. No late morbidity or cardiac toxic effects were found in any patients. After follow-up ranging from 10 months to 14 years, all but 2 of the 51 patients (4%) who received DA-EPOCH-R alone were in complete remission. The 2 remaining patients received radiotherapy and were disease-free at follow-up.Therapy with DA-EPOCH-R obviated the need for radiotherapy in patients with primary mediastinal B-cell lymphoma. (Funded by the National Cancer Institute; ClinicalTrials.gov number, NCT00001337.).

Introduction A high incidence of thyroid dysfunction is reported in patients with HIV or HCV mono-infection. We have conducted a periodic medical examination including the thyroid function for haemophilic patients with HIV/HCV co-infection due to contaminated blood products. Methods We examined the thyroid function (as assessed by the FT3, FT4 and TSH levels) in 45 haemophilic patients, including thyroglobulin and auto-antibody, antithyroglobulin antibody, antithyroid peroxidase antibody and anti-TSH receptor antibody in 28 patients. Results All the patients were males (median age: 42 years; range: 29–66). The median values of thyroid function were FT3 3.36 pg mL−1, FT4 1.125 ng mL−1 and TSH 1.65 μIU mL−1. Five patients (11.1%) had high TSH levels. In 28 patients in whom the presence of auto-antibodies was examined, the median age was 47 years of age. The median value of thyroglobulin was 16 ng mL−1 and two patients showed high levels of thyroglobulin. The presence of anti-TSH receptor antibody of all the patients was negative, but one patient (3.5%) was positive of antithyroid peroxidase antibody and antithyroglobulin antibody. Conclusions Since 0.68–3.6% of the general healthy population is reported to show hypothyroidism, our data showed that the proportion of hypothyroidism in haemophilic patients with HIV/HCV co-infection was more frequent than that of the normal population.

Recently, a genome-wide screening identified a functional single-nucleotide polymorphism in dual-specificity phosphatase 14 gene (DUSP14), which was associated with pulmonary tuberculosis (TB) in a West African study. DUSP14 regulates T-cell proliferation and cytokine production in a negative way via dephosphorylation and inactivation of key signaling molecules. The aim of this study is to further explore the possible significance of the DUSP14 polymorphism. Total RNA was extracted from the whole blood of 109 healthcare workers (HCWs) in Vietnam and subjected to quantitative reverse-transcription PCR for DUSP14 and 20 immune-related genes. DUSP14 rs1051838 was genotyped in 502 new pulmonary TB patients and 506 healthy controls. Among disease-free individuals (HCWs), T-helper type-1 (Th1)-related genes, interferon-gamma receptor 2 (IFNGR2) and signal transducer and activator of transcription-1 (STAT1) mRNA levels significantly increased as the number of A alleles of rs1051838 increased, whereas the DUSP14 mRNA level tended to decrease. The AA genotype was associated with protection against active TB in younger patients (⩽45 years old, OR=0.63, 95% CI 0.44-0.90). Our results suggest that a low-expression genotype of DUSP14 accompanied by high transcript levels of Th1 immune-related genes may confer protection against early TB development.

BACKGROUND AND STUDY AIMS: Conventional colonoscopy can result in unnecessary biopsy or endoscopic resection due to its inability to distinguish adenomas from hyperplastic polyps. This study therefore evaluated the efficacy of high-resolution endoscopy (HRE), autofluorescence imaging (AFI), and narrow-band imaging (NBI) in discriminating colon adenoma from hyperplastic polyps. PATIENTS AND METHODS: This was a prospective multicenter study in patients undergoing AFI and NBI examinations. HRE, AFI, and NBI images were classified into two groups based on morphological characteristics, the predominant color intensities, and the visibility of meshed capillary vessels, respectively. Each of the endoscopic photographs were independently evaluated by a single endoscopist. The images were then assessed by three specialists and three residents, the latter having performed < 500 colonoscopies and < 30 NBI and AFI examinations. Diagnostic test statistics were calculated to compare the accuracy in differentiating colon adenoma from hyperplastic polyps for each method. RESULTS: A total of 183 patients were enrolled in the study and 339 adenomas and 85 hyperplastic polyps were identified. AFI and NBI could distinguish adenoma from hyperplastic polyps with an accuracy of 84.9 % and 88.4 %, respectively, whereas HRE exhibited an accuracy of 75.9 %. In the 358 lesions in which the AFI diagnosis was consistent with that of NBI, the accuracy, sensitivity, and specificity were high, at 91.9 %, 92.7 %, and 92.9 %, respectively. During the study comparing specialists and residents, AFI and NBI dramatically improved the diagnostic accuracy of residents from 69.1 % to 86.1 % and 84.7 %, respectively. CONCLUSIONS: Both AFI and NBI are considered to be feasible tools that can discriminate colon adenoma from hyperplastic polyps, and their use may be particularly beneficial for less-experienced endoscopists.

Systems capable of monitoring the biological condition of a driver and issuing warnings during instances of drowsiness have recently been studied. Moreover, many researchers have reported that biological signals, such as brain waves, pulsation waves, and heart rate, are different between people who have and have not consumed alcohol. Currently, we are developing a noninvasive system to detect individuals driving under the influence of alcohol by measuring biological signals. We used the frequency time series analysis to attempt to distinguish between normal and intoxicated states of a person as the basis of the sensing system.

Several lines of evidence suggest that extracellular ATP plays a role in pain signaling through the activation of ionotropic P2X-receptors, especially homomeric P2X3- and heteromeric P2X2/3-receptors on capsaicin-sensitive and -insensitive primary afferent neurons, respectively, at peripheral and spinal sites. We investigated the mechanisms of the induction and maintenance of mechanical allodynia produced by a single intrathecal (i.t.) administration of ATP in rats. We found that i.t. administration of ATP and the P2X-receptor agonist alpha,beta-methylene-ATP produced tactile allodynia which lasted more than 1 week. The i.t. ATP- and alpha,beta-methylene-ATP-produced long-lasting allodynia remained in neonatal capsaicin-treated adult rats. I.t. administration of a P2X3/P2X2/3-receptor selective antagonist completely prevented the induction (co-administration on day 0) and partially attenuated the early phase (day 1 post-ATP administration), but not the late phase (day 7 post-ATP administration) of maintenance of allodynia. The N-methyl-D-aspartate (NMDA) receptor antagonist MK-801 completely prevented the induction phase, but not the early and late phases of maintenance of allodynia. Immunohistochemical and immunoblotting studies for microglial and astrocytic markers revealed that i.t. ATP administration caused spinal microglial activation within 1 day, and astrocytic activation which peaked at 1-3 days after ATP administration. Furthermore, minocycline, a microglial inhibitor, attenuated the induction but not the early and late phases of maintenance, while fluorocitrate, a glial metabolic inhibitor, attenuated the induction and the early phase but not the late phase of maintenance. Taken together, these results suggest that the activation of P2X-receptors, most likely spinal P2X2/3-receptors on capsaicin-insensitive primary afferent neurons, triggers the induction of long-lasting allodynia through NMDA receptors, and the induction and early maintenance phase, but not the late phase, is mediated through the functions of spinal glial cells.

This study investigates whether the proliferative activity of giant cell tumour of tendon sheath is related to its recurrence rate and local aggressiveness. The clinicopathological and immunohistochemical features of 30 localized giant cell tumours of tendon sheath were studied and the influence of the MIB-1 staining index on recurrence, tumour extent around the phalanx and involvement of the bone were evaluated. No significant difference in the MIB-1 staining index was found between the lesions which recurred and those which did not. Also there was no significant association between local aggressiveness and the MIB-1 staining index. These results suggest that the proliferative activity of localized giant cell tumour of tendon sheath is not related to its high recurrence rate and local aggressiveness.

Background Thromboelastometric evaluation of coagulation might be useful for prediction and management of bleeding after paediatric cardiac surgery. We tested the hypothesis that the use of a thromboelastometry-guided algorithm for blood product management reduces blood loss and transfusion requirements. Methods We studied 78 patients undergoing paediatric cardiac surgery with cardiopulmonary bypass (CPB) for the initial 12 h after operation. Stepwise multiple linear regression was used to develop an algorithm to guide blood product transfusions. Thereafter, we randomly assigned 100 patients to conventional or algorithm-guided blood product management, and assessed bleeding and red cell transfusion requirements. Results CPB time, post-bypass rotational thromboelastometry (ROTEM ® ) EXTEM amplitude at 10 min (A10), and FIBTEM-A10 were independently associated with chest tube drainage volume during the initial 12 h after operation. Discriminative analysis determined cut-off values of 30 mm for EXTEM-A10 and 5 mm for FIBTEM-A10, and estimated optimal intraoperative fresh-frozen plasma and platelet concentrate transfusion volumes. Thromboelastometry-guided post-bypass blood product management significantly reduced postoperative bleeding (9 vs 16 ml kg −1 , P vs 23 ml kg −1 , P =0.005) at 12 h after surgery, and duration of critical care stay (60 vs 71 h, P =0.014). Conclusions Rotational thromboelastometry-guided early haemostatic intervention by rapid intraoperative correction of EXTEM-A10 and FIBTEM-A10 reduced blood loss and red cell transfusion requirements after CPB, and reduced critical care duration in paediatric cardiac surgical patients. Clinical trial registration UMIN Clinical Trials Registry UMIN000006832 (December 4, 2011).

BACKGROUND AND STUDY AIMS The aims of this article were to clarify the incidence of gastric remnant cancer after surgery for early gastric cancer, and to develop surveillance programs for patients who have undergone partial gastrectomy in order to detect such lesions at an early stage. PATIENTS AND METHODS A total of 642 patients with partial gastrectomy for early gastric cancer were enrolled in a surveillance program for gastric remnant cancer between 1985 and 1996. In 509 patients, the interval between endoscopic examinations was no more than 2 years. RESULTS Among the 509 patients examined periodically, 15 patients were diagnosed as having gastric remnant cancer; in 12 patients, the cancers were detected at an early stage. All gastric remnant cancers were found distant from the site of the anastomosis, and in eight patients the cancers were located on the lesser curvature. The cumulative 5-year prevalence rate was estimated as 2.4 % and the 10-year prevalence rate as 6.1 %. The initial tumors in the patients with gastric remnant cancer were of the microscopically intestinal type, without exception. The interval between the preceding examination and diagnosis was shorter in the patients with early cancer than in those with advanced cancer ( P < 0.01). CONCLUSIONS Periodical surveillance endoscopy for gastric remnant cancer is recommended after surgery for early gastric cancer, particularly in patients whose cancers are of the intestinal type. The examinations can be repeated at 2 - 3-year intervals, and special attention should be given to the lesser curvature away from the anastomotic site.

Manual preference and intermanual performance asymmetry have been approached from a multidimensional and dynamic perspective. A point of interest from that approach is the role of lateralized motor experiences on handedness. In this study, intermanual performance asymmetry in sport-specific movements and manual preference in daily living tasks were compared between Kung Fu athletes and novices. Analysis of movement time in the performance of interlaterally symmetric and asymmetric movement patterns showed smaller intermanual performance asymmetry in experts. Analysis of manual preference using the Edinburgh Handedness Inventory indicated that experts presented predominantly weak or moderate strength of right hand preference. Novices, conversely, were found to have predominantly strong right hand preference. These results suggest that extensive bimanual training by experts leads to a global shift of manual preference, affecting hand selection in distinct tasks.

Purpose: To investigate the age and sex dependence of the bone mineral status of human lumbar vertebrae with special regard to differences between cortical and trabecular bone. Material and Methods: The study group comprised 125 normal Japanese healthy volunteers (54 males and 71 females), and was subdivided into adult male and female groups (subjects younger than 40 years), intermediate male and female groups (ages ranging between 41 and 64 years) and old male and female groups (subjects older than 65 years). The cortical bone mineral status was estimated using a single-energy quantitative CT (SE-QCT) technique, whereas trabecular bone mineral density (BMD) was estimated using a dual-energy (DE-QCT) technique. Results: A considerable gender difference in the age-related cortical bone status was found. There was a significant reduction of the mean values of the cortical volume and BMD in the old female group compared with those obtained in the old male group. Conclusion: The results suggest that in men, cortical and trabecular bone volume decrease very little with age. In women, cortical volume and BMD and trabecular BMD decrease with age while trabecular bone volume does not. The study showed that all variables had higher values in men than in women and that the difference increased with age.

To elucidate the genotypic and phenotypic characteristics of autosomal dominant polycystic kidney disease (ADPKD) in Japanese populations, we performed a comprehensive search for mutations in PKD1 and PKD2 in 180 Japanese ADPKD patients from 161 unrelated families. We identified 112 (89 PKD1 and 23 PKD2) mutations within 135 families. Patients with PKD2 mutations account for 23.6% of all Japanese ADPKD families in this study. Seventy-five out of the 112 mutations have not been reported previously. The estimated glomerular filtration rate (eGFR) decline was significantly faster in patients with PKD1 mutations than in those with PKD2 mutations (-3.25 and -2.08 ml min(-1) year(-1) for PKD1 and PKD2, respectively, p 0.01). These results indicate that mutations within PKD1 and PKD2 can be linked to most of the cases of Japanese ADPKD, and the renal function decline was faster in patients with PKD1 mutations than in those with PKD2 mutations also in the Japanese ADPKD. We also found that PKD2 mutations were more frequent in Japanese ADPKD than that in European or American ADPKD.

[3H]Serotonin (5-HT) uptake by synaptosomes of rat brain was dose-dependently inhibited by nitric oxide (NO) donors such as sodium nitroprusside (SNP), 3-(2-hydroxy-1-methyl-2-nitrosohydrazino)-N-methyl-1-propanamin e, 3-morpholinosydnonimine and S-nitroso-L-cysteine (NO-CYS). The inhibitory effect was blocked by reduced hemoglobin. The effect was not mimicked by ferrocyanide and ferricyanide. 8-Bromoguanosine 3',5'-cyclic monophosphate (8-bromo cGMP) did not affect [3H]5-HT uptake into rat cortical synaptosomes. The reduced activity of [3H]5-HT uptake into the cortical synaptosomes pretreated with NO-CYS was partially reversed by washing the preparation after the treatment. Kinetic analysis showed that NO-CYS (100 microM) decreased the Vmax value without any change in the Km value. NO-CYS did not affect the specific binding of [3H]paroxetine, a ligand that binds to the 5-HT transporter, in membranes. NO-CYS and SNP, like iodoacetic acid and sodium cyanide, decreased the ATP content in cortical synaptosomes, but the effect on ATP content was not related to that on [3H]5-HT uptake. These findings suggest that NO inhibits reversibly [3H]5-HT uptake into rat brain synaptosomes without affecting the recognition site of the 5-HT transporter in a cGMP-independent manner, and the observed effect is not due to its metabolic effect.

Effects of morphine and aluminum fluoride on field potentials evoked in hippocampal pyramidal cells were investigated revealing the physiological significance of adenylate cyclase in morphine action. Dibutyryl-cyclic AMP (db-cAMP) reduces the amplitude of potentials, while morphine enhances it. Morphine was without effects on db-cAMP induced reduction of potentials. Aluminum fluoride, known to activate GTP binding proteins, also reduced potentials and this was antagonized by morphine. Furthermore, N-[2-(methylamino)ethyl]-5-isoquinolinesulphonamide dihydrochloride (H-8), a protein kinase A inhibitor, enhanced potentials. When GABA synthesis was inhibited by 3-mercaptopropinoic acid, both morphine and db-cAMP was without effect. These results suggested the inhibition of adenylate cyclase by morphine which might be related with the reduction of GABA release in hippocampal slices.

Oral sumatriptan administration has been reported to delay gastric emptying after liquid meals. The aim of this study was to determine whether delayed gastric emptying is caused by enhanced gastric accommodation, impaired antral contractions, or both using ultrasonography.Ten healthy volunteers were enrolled in this randomized two-way crossover study. After overnight fasting, the subjects received the liquid meal 60 min after ingesting a 50 mg sumatriptan tablet with 50 mL of water or 50 mL of water alone (control). The cross-sectional area of the proximal stomach was measured in a supine position after every 100 mL. The frequency and amplitude of the antral contractions were measured in a slightly backward sitting position. The intragastric distribution of the liquid meal was assessed by calculating the proximal stomach/distal stomach ratio (prox/distal ratio).The cross-sectional area after drinking 100, 200, and 300 mL of the liquid meal (oral sumatriptan vs control) was 34.49 vs 15.11 cm(2) (P = 0.0051), 48.00 vs 30.61 cm(2) (P = 0.0166), and 58.67 vs 47.19 cm(2) (P = 0.0125), respectively. There was no significant difference in the amplitude of contractions, contraction cycle, motility index, and prox/distal ratio (97.15 vs 97.93%, P = 0.0745; 19.42 vs 19.5 s, P= 0.8590; and 887.58 vs 889.22, P = 0.5751; 9.75 vs 8.41, P = 0.8785; respectively).Oral sumatriptan administration enhanced gastric accommodation after the ingestion of liquid nutrients, but had no significant effect on antral contractions or intragastric distribution in healthy subjects.

Patients on hemodialysis (HD) who undergo lung resection represent a high risk group requiring a careful perioperative management. To access a cardiac risk of HD patients a complete cardiac examination must be conducted preoperatively. The patients should undergo sufficient courses of HD to ameliorate electrolyte imbalance and volume disturbance before surgery. An elective operation should be scheduled on the day after HD. During operation, gentle operative maneuver and complete hemostatic technique are required to reduce a risk of postoperative bleeding. An adequate amount of antibiotics should be administrated to avoid a surgical site infection. Pulmonary edema due to volume overload and hyperkalemia are the most dangerous postoperative complications. Infusion should be conducted with potassium-free solution at 20~40 ml/h until the restart of HD. HD could be safely performed with nafamostat mesilate on the day after operation in most patients. If hyperkalemia and pulmonary edema are resistant to conservative managements, an emergency HD is required. Prognosis after lung resection for lung cancer patients on HD is not satisfactory. Many patients die of non cancer related causes such as heart failure and infection. Long term management of the underlying renal condition is necessary to improve their postoperative survival.

A case-controlled study was performed to investigate the association of colonic angiectasia with other conditions and to identify risk factors for bleeding.Information was collected from all patients who underwent colonoscopy at our hospital between January 2008 and December 2010. Data on 90 individuals with angiectasia [58 men; median age 69 (26-92) years] were compared with those of 180 individuals without angiectasia, matched for gender and age.Multivariate analysis showed that occult gastrointestinal bleeding [odds ratio (OR) 2.523; 95% confidence interval (CI) 1.238-5.142], liver cirrhosis (OR 13.195; 95% CI 3.502-49.711), chronic renal failure (OR 6.796; 95% CI 1.598-28.904) and valvular heart disease (OR 6.425; 95% CI 1.028-40.165) were identified as significant predictors of the presence of colonic angiectasia. Eight patients were diagnosed with bleeding from angiectasia. Cardiovascular disease (OR 22.047; 95% CI 1.063-457.345) and multiple angiectasias (P-value 0.0019) were identified as significant risk factors for active bleeding. Medication and a large size were not associated with an increased risk of bleeding.The presence of colonic angiectasia was associated with valvular heart disease, liver cirrhosis and chronic renal failure. Valvular heart disease and multiple lesions increased the risk of bleeding.

Bendamustine is approved in the United States for relapsed indolent lymphoma. However, it has not been widely studied in mantle cell lymphoma (MCL). We retrospectively reviewed the records of all patients with MCL who were treated with bendamustine at three centers. The primary endpoint was overall response rate (ORR). Thirty patients with MCL received bendamustine, 25 for relapsed disease. After a median follow-up of 12 months, there were 15 complete responses (CRs) with an ORR of 83% (95% confidence interval [CI] 70-97%). Factors significantly associated with longer survival were achieving a CR and classical (versus blastic) variant of MCL. Grade 3 or 4 neutropenia, anemia and thrombocytopenia occurred in 23%, 3% and 20%, respectively. There was one case of progressive multifocal leukoencephalopathy 10 months after therapy completion. Bendamustine in combination with rituximab demonstrated a high response rate in this study of patients with predominantly relapsed MCL.

OBJECTIVE: There are various options for the treatment of vertebral artery dissection aneurysms (VADA). Treatment with stents may be an effective method to treat VADA involving the posterior inferior cerebellar artery (PICA) and dissection of the dominant vertebral artery (VA). In this article, our personal experience of the treatment of VADAs by using stents and coils is reported. METHODS: Since 1998, 26 cases of VADA have been treated by endovascular surgery by the first author. Of these cases, 6 cases were treated using stents, 3 of which were treated using stent and coils, 2 patients were treated using double overlapping stents, and the remaining one patient was treated using a single stent. RESULTS: In all patients, dissection aneurysms were successfully covered by stents. There was one complication: an intraprocedural rupture during additional coil insertion without neurological deterioration. Follow-up angiography was performed in all 5 surviving patients except for one patient who died due to the severity of his original subarachnoid hemorrhage (mean duration of follow-up angiography 22.8 months, range 15-57 months). Total or subtotal disappearance of the VADA was achieved in all 5 cases. At one year after the treatment, all 5 surviving patients remained clinically stable without any neurological deficit. CONCLUSIONS: Treatment using stents is an effective alternative for the treatment of VA dissecting aneurysms, especially for lesions of the dominant VA or involving the PICA. However, additional coil insertion should be performed very carefully and may be avoided if stagnation of contrast material is achieved after overlapping stenting.

Purpose In the United States, early-stage Hodgkin's lymphoma (HL) is defined as asymptomatic stage I/II non-bulky disease. European groups stratify patients to more intense treatment by considering additional unfavorable factors, such as age, number of nodal sites, sedimentation rate, extranodal disease, and elements of the international prognostic score for advanced HL. We sought to determine the prognostic significance of these factors in patients with early-stage disease treated at Stanford University Medical Center. Methods and Materials This study was a retrospective analysis of 101 patients treated with abbreviated Stanford V chemotherapy (8 weeks) and 30-Gy ( n = 84 patients) or 20-Gy ( n = 17 patients) radiotherapy to involved sites. Outcomes were assessed after applying European risk factors. Results At a median follow-up of 8.5 years, freedom from progression (FFP) and overall survival (OS) rates were 94% and 97%, respectively. From 33% to 60% of our patients were unfavorable per European criteria (i.e., German Hodgkin Study Group [GHSG], n = 55%; European Organization for Research and Treatment of Cancer, n = 33%; and Groupe d'Etudes des Lymphomes de l'Adulte, n = 61%). Differences in FFP rates between favorable and unfavorable patients were significant only for GHSG criteria ( p = 0.02) with there were no differences in OS rates for any criteria. Five of 6 patients who relapsed were successfully salvaged. Conclusions The majority of our patients deemed unfavorable had an excellent outcome despite undergoing a significantly abbreviated regimen. Application of factors used by the GHSG defined a less favorable subset for FFP but with no impact on OS. As therapy for early-stage disease moves to further reductions in therapy, these factors take on added importance in the interpretation of current trial results and design of future studies.

Surgical approach is one of the most crucial aspects in the treatment of superior sulcus tumor (SST). Posterior approach as described by Paulson and coworkers is appropriate for the resection of SST invading posterior part of the 1st rib and the vertebrae, whereas anterior approaches as described by Masaoka, Dartevelle, Grunenwald, or Rusca are suitable for resection of SST involving subclavian vessels. We present 2 cases of SST who underwent complete resection through the posterior approach and a modified hemi-clamshell approach, respectively. We also discuss the surgical approaches for SST with referring to literatures.

Systolic anterior motion of the anterior mitral leaflet and asymmetric septal hypertrophy (ASH) are characteristic features of hypertrophic obstructive cardiomyopathy (HOCM) on an echocardiogram. Among 9,670 patients over 60 years old examined by echocardiography from January, 1984 to October, 1990, 55 patients showed systolic anterior motion of the anterior mitral leaflet and/or the chordae tendinae (SAM). We investigated clinical features and morphological features of the left ventricle on an echocardiogram in the 55 patients with SAM. They were classified into three groups according to the degree of SAM. Thirty eight cases (group I) had no mitral and/or chordal-septal contact, 10 (group II) had brief contact (less than 30% on the echocardiographic systole) and 7 (group III) had prolonged contact (greater than or equal to 30%). Ages ranged from 60 to 99 with a mean age of 78.2 years. There were 19 males and 36 females and there was a predominance of females in each group. Thirty five cases had hypertension and 34 left ventricular hypertrophy on electrocardiograms. One case of group I, 3 of group II and 7 of group III had a clinical diagnosis of HOCM. In comparison with each group, the incidence of LVH (SV1 + RV5 greater than or equal to 35 mm) was 52% in group I, 90% in group II and 83% in group III and that of LVH (SV1 + RV5 greater than or equal to 70 mm) was 29%, 20% and 67%, respectively. On echocardiographic examination, the diastolic descent rate of the anterior mitral leaflet in the 3 groups was 36.1 +/- 13.1 mm/sec, 19.4 +/- 13.1 mm/sec and 10.7 +/- 11.8 mm/sec (p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Shinjuku City, Tokyo, Japan.To evaluate the status of transmission of Mycobacterium tuberculosis in Shinjuku City to allocate resources efficiently and effectively for a successful tuberculosis (TB) control programme.Observational descriptive study combining the genotype data of M. tuberculosis with TB patient profiles.The genotype clustering rate was significantly higher in males (adjusted odds ratio [aOR] 1.94, 95%CI 1.04-3.65, P = 0.038), patients aged40 years (aOR 2.09, 95%CI 1.17-3.71, P = 0.012) and the homeless (aOR 2.72, 95%CI 1.42-5.20, P = 0.002), and was lower for the foreign-born (aOR 0.21, 95%CI 0.06-0.76, P = 0.017). Among 45 genotype clusters containing 152 TB patients, 26 clusters containing 102 patients (67.1%) were composed of a mix of homeless and non-homeless patients. One of the mixed clusters included an 8-month-old infant born in Japan.The study revealed that M. tuberculosis transmission occurred more frequently among the homeless than in non-homeless persons. However, transmission by casual contact between the homeless and the general population was also shown to occur.

Lymphocyte subsets defined by monoclonal antibodies were investigated in bone marrow and peripheral blood of 17 patients with rheumatoid arthritis (RA); 13 patients with osteoarthritis or aseptic necrosis served as controls. Patients with RA were found to have a raised OKT 4/8 ratio both in bone marrow and peripheral blood in comparison with the controls. Furthermore, bone marrow of RA showed a lower percentage of OKT 8+ T cells than that of controls. The percentage of HLA-DR+ T cells was higher in bone marrow than in peripheral blood of RA, though a slightly lower percentage was detected in bone marrow than in peripheral blood of controls. Thus T cell subsets in bone marrow of RA differ significantly from those of controls. Patients with RA had a higher OKT 4/8 ratio and a higher percentage of HLA-DR+ T cells in bone marrow than controls, suggesting that T cell subsets in bone marrow of RA are in an immunologically activated state and that T cell subsets are affected by rheumatoid inflammation in bone marrow of RA.

Schwannoma is a benign neurogenic tumor arising from the sheath of peripheral nerves. It occurs very rarely in the mesentery, where it is difficult to diagnose. Herein we describe a case in which contrast-enhanced CT and gadolinium-DTPA-enhanced MR showed a locally enhanced well-defined tumor with a cystic component just anterior to the duodenum. These findings corresponded well to the resected specimen.

BACKGROUND: A combination of bronchodilators may be effective in the treatment of chronic obstructive pulmonary disease (COPD). We examined the effect of adding a long-acting anti-cholinergic agent (tiotropium) to a transdermal-type beta(2)-agonist (tulobuterol) on dyspnea as well as pulmonary function. METHODS: In a multicentre, randomized, parallel design study, 60 COPD patients treated with the transdermal beta(2)-agonist tulobuterol were divided into a tiotropium added group (Tulo+Tio group, n=40) or transdermal beta(2)-agonist tulobuterol alone group (Tulo group, n=20), and then treated for 4 weeks after a 2 week run-in period. Pulmonary function and a dyspnea (Medical Research Council (MRC)) scale were assessed before and after the treatment. Daily peak expiratory flow (PEF) monitoring was also performed. RESULTS: After 4 weeks, the Tulo+Tio group showed a significant increase in pulmonary function compared with the Tulo group; DeltaFVC (0.31+/-0.06 L vs. 0.06+/-0.05 L, p< 0.01), DeltaFEV(1) (0.15+/-0.03 L vs. -0.02+/-0.02 L, p

A computed tomography (CT) and high-resolution CT (HRCT) have provided us an increasing opportunity to find multiple small pulmonary nodules, which sometimes appear ground glass opacity (GGO). Recently, fluorodeoxyglucose-positron emission tomography (FDG-PET) had a great contribution to our assessment for these small pulmonary nodules. However, since it is yet difficult to establish a diagnosis for these nodules during preoperative workup, a surgical lung biopsy is often required for an accurate diagnosis. We have experienced 9 patients who had undergone lung resection for primary lung cancer accompanied by multiple pulmonary lesions. Since the multiple lesions were consisted of malignant and benign lesions, it is still uncertain whether excessive lung resection should be performed in such patients. In this brief article, we summarized the characteristics of the pulmonary lesions in those patients and discussed difficulty of preoperative diagnosis, viability of pulmonary resection and problems underlining a surgical treatment.

Intrathoracic extramedullary hematopoiesis is a rare condition accompanying chronic hematologic disease. We present a case of chronic gastric ulcer in which a posterior mediastinal mass was diagnosed as extramedullary hematopoiesis. We underwent video-assisted thoracoscopic resection safely and successfully. This procedure is relevant and safety procedure for differential diagnosis of patients who have chronic anemia with asymptomatic intrathoracic tumors.

To evaluate the susceptibility of patient with focal interstitial pneumonia (IP) to postoperative acute exacerbation, and to determine whether measuring serum level of several markers is useful for early detection of postoperative IP or not, we analyzed a total of 753 patients with primary lung cancer underwent thoracotomy. Twelve (1.6%) had postoperative IP. Eight of the 12 died due to IP and 9 of the 12 had focal IP findings on chest computed tomography (CT). Chest CT of 477 patients were reviewed retrospectively, and 51 (10.7%) had IP findings (diffuse 2.1%, focal 8.6%). Postoperative IP occurred in 17.6% of patients with IP findings, but only in 0.7% without such findings (p0.01). Values of serum KL-6 decreased after lung resection. There were no changes in the value of serum TNF-alpha, IL-1beta, thrombomodulin and sICAM-1 after surgery. We conclude that focal IP is a risk factor of postoperative IP, and that it is not useful to measure serum markers for early detection of postoperative IP.

The Modelflow method can estimate cardiac output from arterial blood pressure waveforms using a three-element model of aortic input impedance (aortic characteristic impedance, arterial compliance, and systemic vascular resistance). We tested the reliability of a non-invasive cardiac output estimation during submaximal exercise using the Modelflow method from finger arterial pressure waveforms collected by Portapres in healthy young humans.The Doppler echocardiography method was used as a reference method. Sixteen healthy young subjects (nine males and seven females) performed a multi-stage cycle ergometer exercise at an intensity corresponding to 70, 90, 110 and 130% of their individual ventilatory threshold for 2 min each. The simultaneous estimation of cardiac output (15 s averaged data) using the Modelflow and Doppler echocardiography methods was performed at rest and during exercise.The Modelflow-estimated cardiac output correlated significantly with the simultaneous estimates by the Doppler method in all subjects (r = 0.87, P0.0001) and the SE of estimation was 1.93 L min-1. Correlation coefficients in each subject ranged from 0.91 to 0.98. Although the Modelflow method overestimated cardiac output, the errors between two estimates were not significantly different among the exercise levels. These results suggest that the Modelflow method using Portapres could provide a reliable estimation of the relative change in cardiac output non-invasively and continuously during submaximal exercise in healthy young humans, at least in terms of the relative changes in cardiac output.

Background and study aims In difficult cases of selective bile duct cannulation, several expanded techniques are available which have only been partially evaluated in randomized studies. This study describes a prospective, randomized trial investigating a further technique for obtaining selective biliary access--pancreatic duct wire placement. Patients and methods During a six-month study period, 107 consecutive patients required deep selective biliary cannulation. Accessing the bile duct using a catheter failed within 10 min in 53 of the patients, who were randomly assigned to either pre-insertion of a guide wire into the pancreatic duct or persistence with a conventional catheter. The success rate and complication rate were compared between these two groups. Results In the pancreatic duct-guide wire group (n=27), the success rate was significantly greater than in the conventional group (93% vs 58%). No pancreatitis complications occurred within either group. Conclusions Inserting a guide wire into the pancreatic duct to facilitate deep selective bile duct cannulation is better than persisting with a conventional catheter. Further studies will be needed to confirm these results and to compare this method with other sophisticated techniques for obtaining selective access to the bile duct.

The purpose of this study was to determine what patterns of perceptual confusions characterize the voice of patients after supracricoïd partial laryngectomy (SCPL) by the identification tests of French consonants. We evaluated the voicing distinction.Ten male patients were recorded 18 months after SCPL. Audio recordings of the 16 French consonants in a syllabic context (CV) produced by each talker with three repetitions were presented to three expert listeners. The listeners transcribed their responses using an open-response paradigm. Listeners' pooled responses were converted to confusion matrices.Voicing features were altered with a shift of voiced consonants towards voiceless consonants (24%), predominantly for stop consonants.Consonant articulation appears to impose certain constraints on voicing ability of SCPL patients, since voiced consonants are predominantly perceived as voiceless consonants. Presumably, this poor voicing ability is the direct consequence of the mechanical properties of the neoglottis that are far different from those of the vocal folds. Moreover, assessing consonant identification and intelligibility should help to improve voice therapy and efficiency of speech.

Ageing impairs endothelial function such as the regulation of vascular tone. The release of nitric oxide (NO), which has a potent vasodilator effect and antiatherosclerotic property, is decreased in the aorta of aged rats. Exercise training, however, has been reported to increase the expression of endothelial NO synthase (eNOS) in the aorta of young rats. In aged rats, it is not known whether the expression of eNOS is altered by exercise training. We hypothesized that exercise training would improve the ageing-induced decrease in eNOS expression in vessels, and examined the messenger RNA (mRNA) and protein expression of eNOS in the aorta of sedentary-young rats (sedentary-young group; 4 months old), sedentary-aged rats (sedentary-aged group; 23 months old), and swim-trained aged rats (training-aged group; 23 months old, swimming training for 8 weeks, 5 days week(-1), 90 min day(-1)).Body weight was significantly lower, and citrate synthase activity in the epitrochlearis muscle was significantly higher in the training-aged group compared with the sedentary-aged group. The mRNA expression of eNOS in the aorta was significantly higher in the training-aged group than in the sedentary-aged group, while it was significantly lower in both the sedentary-aged and training-aged groups than in the sedentary-young group. The expression of eNOS protein in the aorta was also significantly higher in the training-aged group than in the sedentary-aged group, while it was also significantly lower in the sedentary-aged group, but not in the training-aged group, than in the sedentary-young group.The present results revealed that the production of eNOS in the aorta decreases with ageing, and that the decreased production is increased by exercise training in aged rats, which may produce beneficial effects on the impaired cardiovascular system caused by ageing.

We have performed pulmonary metastasectomy on 97 patients with various malignant tumors. We analyzed the outcome of surgical treatment and prognostic factors. Survival of patients undergoing metastasectomy was significantly different according to the type of malignant tumor. The patients with carcinomas had a good survival when they had 3 years or longer disease free interval (DFI) and no other lesion except the lungs. Those with sarcomas were good survivors, who had a solitary pulmonary lesion, 1 years or longer DFI, and had no symptom originating from pulmonary metastases. Survival of patients with germ cell tumors was significantly superior to other 2 types, and factors such as an existence of extra-pulmonary metastatic lesions, respiratory symptoms and a length of DFI had no impact on the chance of their survival. These results suggest that we should decide the indication for metastasectomy on patients according to their types of malignant tumor.

The sex chromosome constitution of the silkworm, Bombyx mori, is ZW in the female and ZZ in the male. Very little molecular information is available about the Z chromosome in Lepidoptera, although the topic is interesting because of the absence of gene dosage compensation in this chromosome. We constructed a 320-kb BAC contig around the Bmkettin gene on the Z chromosome in Bombyx and determined its nucleotide sequence by the shotgun method. We found 13 novel protein-coding sequences in addition to Bmkettin. All the transposable elements detected in the region were truncated, and no LTR retrotransposons were found, in stark contrast to the situation on the W chromosome. In this 320-kb region, four genes for muscle proteins (Bmkettin, Bmtitin1, Bmtitin2, and Bmprojectin) are clustered, together with another gene (Bmmiple) on the Z chromosome in B. mori; their orthologs are also closely linked on chromosome 3 in Drosophila, suggesting a partial synteny. Real-time RT-PCR experiments demonstrated that transcripts of 13 genes of the 14 Z-linked genes found accumulated in larger amounts in males than in female moths, indicating the absence of gene dosage compensation. The implications of these findings for the evolution and function of the Z chromosome in Lepidoptera are discussed.

To assess the relationship between the histological features of renal chromophobe cell carcinoma (CCC) and clinical outcome in patients with renal cell carcinoma.From 1957 to 1996, 41 patients with CCC of the kidney (4.9% of all kidney carcinomas) were treated at our university hospitals. Of these histologically defined cases, four who died from other types of cancer and two who were lost to follow-up were excluded, leaving 35 patients in the study; the carcinoma was classified as the typical variant in 26 and the eosinophilic variant in nine. Based on the differences of the variants, the histological features affecting prognosis were analysed.The overall survival rates at 1, 3, 5, 10, 15 and 20 years were 97%, 82%, 82%, 70%, 62% and 47%, respectively. The prognosis was more favourable in those with the eosinophilic than for the typical variant (there were no cancer-related deaths in the former). Of those with the typical variant, five died within 2 years of surgery; of these, three with high-stage disease had various degrees of sarcomatoid change. Conversely, two patients had a recurrence10 years after surgery (late recurrence). Both these patients and the others who later died from cancer had no sarcomatoid change in the tumour areas examined.The eosinophilic variant of CCC has a better prognosis; on the contrary, during long-term surveillance, early recurrence was detected especially in those with sarcomatoid change and late recurrence only in two typical variant. These prognostic implications of the histological differences are important for understanding the outcome of renal CCC.

During the last few years, video-assisted neck surgery (VANS) became one option for thyroid and parathyroid surgery. Reports on VANS were limited to partial resection of the thyroid gland. In this study, we described total thyroidectomy in a patient with Graves' disease. The patient had a thyrotoxic periodic paralysis and methimazole-induced hepatic toxicity as well as hepatitis B virus. Two incisions of 3.5 and 3 cm were placed in the right and left subclavicular regions, respectively. A third incision of 0.5 cm was made just to the right of the midline for the camera. Devascularization of the thyroid gland was performed by using ultrasonically activated shear. Tubal drains were inserted on both sides. The patient suffered from temporary postoperative hoarseness with the voice but had a normal calcium level. The drains were removed on the first postoperative day. The use of VANS may provide a new method for total thyroidectomy with a better cosmetic outcome.

Ossifying fibromyxoid tumor (OFMT) of soft parts is a rare, recently defined, fibroosseous neoplasm, generally regarded as clinically benign; however, one-third of cases recur locally, and several malignant examples have been reported. Fine needle aspiration (FNA) cytology of the tumor is rarely described in the literature. We provide the first cytomorphologic study of the malignant variant.A 70-year-old man presented with an intramuscular mass in the right buttock. Computed tomography revealed ossification within the mass and multiple pulmonary nodules. FNA biopsy showed round and polygonal to spindled tumor cells, arrayed singly, cordlike or in small aggregates, with scattered dense stromal fragments and a slightly myxoid background. The nuclei showed significant pleomorphism accompanied by coarse chromatin with clumping, irregular contours, and one to two distinct nucleoli. The tumor cells were recognizable as sarcoma, with no evidence of high grade malignancy. The tumor was totally excised, histopathologically confirmed as the malignant variant of OFMT of soft parts, and immunohistochemically and ultrastracturally analyzed as of neural origin.The FNA specimen revealed that the cytomorphology was consistent with the histologic features of the malignant variant of OFMT, but several characteristic histologic parameters, such as multilobular proliferation and peripherally placed mature, bony trabeculae, were not reflected in the aspirates. Although FNA cytologic findings may be of limited diagnostic utility in OFMT, radiographic evidence of calcification/ossification suggests that OFMT should be subjected to differential diagnosis with fine needle aspiration biopsy of soft tissue tumors. Additional studies will be required for further clarification.