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In this study, we evaluated different machine learning algorithms for touch classification using data obtained with the upper part of a whole-body sensor suit for human-looking robots and gathered human touch interaction data, comparing the results with human classification based on video footage. The data collection experiment included eight different touch behaviors: hit, hug, pat, poke, push, shake, tap, and sexual harassment (SH). Two different datasets were defined based on the data gathered: instant dataset which is the exact moment when the touch is performed and average dataset which is the average of ~1 s before and after of the touch interaction. Seven different machine-learning algorithms were implemented: logistic regression (LR), linear support vector machine (L_SVM), random forest classifier (RFC), one-vs-rest (OVR) classifier, kernelized support vector machine (K_SVM), K-nearest neighbors (KNNs), and fully connected neural network (FCNN). The results obtained showed that the FCNN has the best performance in both datasets, having the higher score with the average dataset. Finally, this result was compared with the human classification results, which had a considerably lower accuracy, showing that the implementation of a neural network with the sensor suit can lead to efficient touch behavior classification in human-robot interaction.

Cystic fibrosis (CF) is an autosomal recessive disease caused by pathogenic variants in CF transmembrane conductance regulator(CFTR). While CF is the most common hereditary disease in Caucasians, it is rare in East Asia. In the present study, we have examined clinical features and the spectrum of CFTRvariants of CF patients in Japan. Clinical data of 132 CF patients were obtained from the national epidemiological survey since 1994 and CF registry. From 2007 to 2022, 46 patients with definite CF were analyzed for CFTRvariants. All exons, their boundaries, and part of promoter region of CFTRwere sequenced and the presence of large deletion and duplications were examined by multiplex ligation-dependent probe amplification. CF patients in Japan were found to have chronic sinopulmonary disease (85.6%), exocrine pancreatic insufficiency (66.7%), meconium ileus (35.6%), electrolyte imbalance (21.2%), CF-associated liver disease (14.4%), and CF-related diabetes (6.1%). The median survival age was 25.0 years. The mean BMI percentile was 30.3%ile in definite CF patients aged < 18 years whose CFTRgenotypes were known. In 70 CF alleles of East Asia/Japan origin, CFTR-dele16-17a-17b was detected in 24 alleles, the other variants were novel or very rare, and no pathogenic variants were detected in 8 alleles. In 22 CF alleles of Europe origin, F508del was detected in 11 alleles. In summary, clinical phenotype of Japanese CF patients is similar to European patients, but the prognosis is worse. The spectrum of CFTRvariants in Japanese CF alleles is entirely different from that in European CF alleles.

Emotional voice conversion (VC) aims to convert a neutral voice to an emotional one while retaining the linguistic information and speaker identity. We note that the decoupling of emotional features from other speech information (such as content, speaker identity, etc.) is the key to achieving promising performance. Some recent attempts of speech representation decoupling on the neutral speech cannot work well on the emotional speech, due to the more complex entanglement of acoustic properties in the latter. To address this problem, here we propose a novel Source-Filter-based Emotional VC model (SFEVC) to achieve proper filtering of speaker-independent emotion cues from both the timbre and pitch features. Our SFEVC model consists of multi-channel encoders, emotion separate encoders, pre-trained speaker-dependent encoders, and the corresponding decoder. Note that all encoder modules adopt a designed information bottleneck auto-encoder. Additionally, to further improve the conversion quality for various emotions, a novel training strategy based on the 2D Valence-Arousal (VA) space is proposed. Experimental results show that the proposed SFEVC along with a VA training strategy outperforms all baselines and achieves the state-of-the-art performance in speaker-independent emotional VC with nonparallel data.

We report a case of sustained complete response in unfavorable cancer of unknown primary site (CUP) successfully treated with chemotherapy combining pembrolizumab, pemetrexed and platinum.

This paper outlines an augmented robotic architecture to study the conditions of successful Human-Humanoid Interaction (HHI). The architecture is designed as a testable model generator for interaction centred on the ability to emit, display and detect honest signals. First we overview the biological theory in which the concept of honest signals has been put forward in order to assess its explanatory power. We reconstruct the application of the concept of honest signalling in accounting for interaction in strategic contexts and in laying bare the foundation for an automated social metrics. We describe the modules of the architecture, which is intended to implement the concept of honest signalling in connection with a refinement provided by delivering the sense of co-presence in a shared environment. Finally, an analysis of Honest Signals, in term of body postures, exhibited by participants during the preliminary experiment with the Geminoid Hi-1 is provided.

With recent advances in social robotics, many studies have investigated techniques for learning top-level multimodal interaction logic by imitation from a corpus of human-human interaction examples. Most such studies have taken the approach of learning equally from a variety of demonstrators, with the effect of reproducing a mixture of their average behavior. However, in many scenarios it would be desirable to reproduce specific interaction styles captured from individuals. In this paper, we train one deep neural network jointly on two separate corpuses collected from demonstrators with differing interaction styles. We show that training on both corpuses together improves performance in terms of generating socially appropriate behavior even when reproducing only one of the two styles. Furthermore, the trained neural network also enables us to synthesize new interaction styles on a continuum between the two demonstrated interaction styles. We discuss plots of the hidden layer activations from the neural network, indicating the types of semantic information that appear to be learned by the system. Further, we observe that the better performance with the synthesized corpus is not merely due to the increase of the sample size, as even with the same number of training examples, training on half the data from each corpus provided better performance than training on all the data from a single corpus.

A massive deletion over three exons 16-17b in the CFTRgene was identified in Japanese CF patients with the highest frequency (about 70% of Japanese CF patients definitely diagnosed). This pathogenic mutation results in a deletion of 153 amino acids from glycine at position 970 (G970) to threonine at 1122 (T1122) in the CFTR protein without a frameshift. We name it Δ(G970-T1122)-CFTR. In the present study, we characterized the Δ(G970-T1122)-CFTR expressed in CHO cells using immunoblots and a super resolution microscopy. Δ(G970-T1122)-CFTR proteins were synthesized and core-glycosylated but not complex-glycosylated. This observation suggests that the Δ(G970-T1122) mutation can be categorized into the class II mutation like ΔF508. However, VX-809 a CFTR corrector that can help maturation of ΔF508, had no effect on Δ(G970-T1122). Interestingly C-terminal FLAG tag seems to partially rescue the trafficking defect of Δ(G970-T1122)-CFTR; however the rescued Δ(G970-T1122)-CFTR proteins do not assume channel function. Japanese, and perhaps people in other Asian nations, carry a class II mutation Δ(G970-T1122) with a higher frequency than previously appreciated. Further study of the Δ(G970-T1122)-CFTR is essential for understanding CF and CFTR-related diseases particularly in Asian countries.

It is estimated that up to 5% of cystic fibrosis transmembrane conductance regulator (CFTR) pathogenic alleles are unidentified. Some of these errors may lie in noncoding regions of the locus and affect gene expression. To identify regulatory element variants in the CFTRlocus, SureSelect targeted enrichment of 460 kb encompassing the gene was optimized to deep sequence genomic DNA from 80 CF patients with an unequivocal clinical diagnosis but only one or no CFTR-coding region pathogenic variants. Bioinformatics tools were used to identify sequence variants and predict their impact, which were then assayed in transient reporter gene luciferase assays. The effect of five variants in the CFTRpromoter and four in an intestinal enhancer of the gene were assayed in relevant cell lines. The initial analysis of sequence data revealed previously known CF-causing variants, validating the robustness of the SureSelect design, and showed that 85 of 160 CF alleles were undefined. Of a total 1737 variants revealed across the extended 460-kb CFTRlocus, 51 map to known CFTR cis-regulatory elements, and many of these are predicted to alter transcription factor occupancy. Four promoter variants and all those in the intestinal enhancer significantly repress reporter gene activity. These data suggest that CFTRregulatory elements may harbor novel CF disease–causing variants that warrant further investigation, both for genetic screening protocols and functional assays.

HCO3−secretion in distal airways is critical for airway mucosal defense. HCO3−/H+transport across the apical membrane of airway surface epithelial cells was studied by measuring intracellular pH in luminally microperfused freshly dissected mice bronchioles. Functional studies demonstrated that CFTR, ENaC, Cl−–HCO3−exchange, Na+-H+exchange, and Na+–HCO3−cotransport are involved in apical HCO3−/H+transport. RT-PCR of isolated bronchioles detected fragments from Cftr, α, β, γ subunits of ENaC, Ae2, Ae3, NBCe1, NBCe2, NBCn1, NDCBE, NBCn2, Nhe1, Nhe2, Nhe4, Nhe5, Slc26a4, Slc26a6, and Slc26a9. We assume that continuous decline of intracellular pH following alkaline load demonstrates time course of HCO3−secretion into the lumen which is perfused with a HCO3−-free solution. Forskolin-stimulated HCO3−secretion was substantially inhibited by luminal application of CFTRinh-172 (5 μM), H2DIDS (200 μM), and amiloride (1 μM). In bronchioles from a cystic fibrosis mouse model, basal and acetylcholine-stimulated HCO3−secretion was substantially impaired, but forskolin transiently accelerated HCO3−secretion of which the magnitude was comparable to wild-type bronchioles. In conclusion, we have characterized apical HCO3−/H+transport in native bronchioles. We have demonstrated that cAMP-mediated and Ca2+-mediated pathways are involved in HCO3−secretion and that apical HCO3−secretion is largely mediated by CFTR and H2DIDS-sensitive Cl−–HCO3−exchanger, most likely Slc26a9. The impairment of HCO3−secretion in bronchioles from a cystic fibrosis mouse model may be related to the pathogenesis of early lung disease in cystic fibrosis.

The research and development of robots that can have daily dialogues autonomously with humans have become increasingly important. Most of them, however, have been limited to studies on speech recognition and interfaces. As the result, they still cannot build relationships with humans through long-term daily dialogue. In this background, we have developed a robot that can understand human relationships with their intentions and desires, and can interact with them in human-like ways through various modalities. In this chapter, we first describe an android platform for multimodal interaction based on intentions and desires. Here, both the user’s and the robot’s subjective preferences and opinions are essential. Then, we introduce a function to model the user’s preference, which is necessary for building human relationships. We also discuss the relationship between dialogue and the opinions that can be attributed to the android considering its embodiment. Finally, based on the above studies, we discuss the embodiment in dialogue and future work.

Many human augmentation devices have been developed in the past few decades, but lots of them neglected the importance of well-timed assistance, which commonly leads to problems like lowered performance or interference with user's movement. In this research the authors focused in depth on the timing issue of powered assistance. As a pilot study for the proof of concept, the authors hypothesized that different timing of assistance may greatly affect the efficiency of movement for power-assisting devices, and verified the hypothesis through human experiment on sit-to-stand (STS) movement. By measuring the electromyogram (EMG) of lower limb muscles, the authors firstly confirmed the effectiveness of assistance, then compared the effect of assistance timing with other frequently investigated determinants of STS movement, and evaluated the efficiency of movement under different timing conditions. The results demonstrated the importance of timing in powered assistance, and showed that, rather than the common practice of providing assistance after the onset of movement, which is adopted by most traditional proportional-EMG-controlled human augmentation devices, it may improve the efficiency of movement for at least half of the subjects simply by adopting an earlier (before or at the same time of movement onset) but optimal timing for assistance. As a preparation for future works, the authors also quantitatively analyzed various early timing conditions, and the result indicated that if the authors could realize appropriate movement prediction mechanism, the performance of assistance may be improved further. Considering the generality of timing issue in many related works, these results could lead to a new direction of research on performance improvement of human augmentation devices.

This paper proposes a learning from demonstration system based on a motion feature, called phase transfer sequence. The system aims to synthesize the knowledge on humanoid whole body motions learned during teacher-supported interactions, and apply this knowledge during different physical interactions between a robot and its surroundings. The phase transfer sequence represents the temporal order of the changing points in multiple time sequences. It encodes the dynamical aspects of the sequences so as to absorb the gaps in timing and amplitude derived from interaction changes. The phase transfer sequence was evaluated in reinforcement learning of sitting-up and walking motions conducted by a real humanoid robot and compatible simulator. In both tasks, the robotic motions were less dependent on physical interactions when learned by the proposed feature than by conventional similarity measurements. Phase transfer sequence also enhanced the convergence speed of motion learning. Our proposed feature is original primarily because it absorbs the gaps caused by changes of the originally acquired physical interactions, thereby enhancing the learning speed in subsequent interactions.

Activity recognition, involving a capability to recognize people's behavior and its underlying significance, will play a crucial role in facilitating the integration of interactive robotic artifacts into everyday human environments. In particular, social intelligence in recognizing affectionate behavior will offer value by allowing companion robots to bond meaningfully with interacting persons. The current article addresses the issue of designing an affectionate haptic interaction between a person and a companion robot by exploring how a small humanoid robot can behave to elicit affection while recognizing touches. We report on an experiment conducted to gain insight into how people perceive three fundamental interactive strategies in which a robot is either always highly affectionate, appropriately affectionate, or superficially unaffectionate (emphasizing positivity, contingency, and challenge, respectively). Results provide insight into the structure of affectionate interaction between humans and humanoid robots—underlining the importance of an interaction design expressing sincere liking, stability and variation—and suggest the usefulness of novel modalities such as warmth and cold.

Small robots are being designed to recognize behaviors through playful interaction. Prior work used data from impoverished sensing devices such as inertial sensors to analyze gestures and attitude in playful interaction through time series analysis. However, the prior work did not focus on individual differences required for person identification. This research hypothesizes that person identification can be achieved by determining individual differences in playful interaction by using inertial sensor data. We propose a method that iteratively narrows down the candidates during interaction to achieve accurate person identification. This method calculates the features using a time series of the inertial sensor data. These features identify a candidate who is playfully interacting with the robot using a decision tree classifier that includes combinations of the current candidates. The system stores the results as a dataset for voting, and the voting results are used to reduce the candidates until the number of candidates is winnowed to one. Evaluation results show that our proposed method identifies persons through playful interactions with 99.1% accuracy.

Mutation in the Pkhd1gene that encodes a ciliary protein, fibrocystin, causes multiple cysts in the kidneys and liver in the polycystic kidney (PCK) rat, a model for human autosomal recessive PCK disease. To clarify the role of primary cilia in the pancreatic duct, we examined the structure and function of the exocrine pancreas of PCK rats.

During conversations, speakers employ a number of verbal and nonverbal mechanisms to establish who participates in the conversation, when, and in what capacity. Gaze cues and mechanisms are particularly instrumental in establishing the participant roles of interlocutors, managing speaker turns, and signaling discourse structure. If humanlike robots are to have fluent conversations with people, they will need to use these gaze mechanisms effectively. The current work investigates people's use of key conversational gaze mechanisms, how they might be designed for and implemented in humanlike robots, and whether these signals effectively shape human-robot conversations. We focus particularly on whether humanlike gaze mechanisms might help robots signal different participant roles, manage turn-exchanges, and shape how interlocutors perceive the robot and the conversation. The evaluation of these mechanisms involved 36 trials of three-party human-robot conversations. In these trials, the robot used gaze mechanisms to signal to its conversational partners their roles either of two addressees, an addressee and a bystander, or an addressee and a nonparticipant. Results showed that participants conformed to these intended roles 97% of the time. Their conversational roles affected their rapport with the robot, feelings of groupness with their conversational partners, and attention to the task.

The pancreatic duct epithelium is remarkable for its capacity to secrete HCO3−ions at concentrations as high as 140 mmol/l. The properties of the key transporters involved in this process and the central role played by cystic fibrosis transmembrane conductance regulator (CFTR) are the main focus of this review.

Human behaviors consist of both voluntary and involuntary motions. Almost all behaviors of task-oriented robots, however, consist solely of voluntary motions. Involuntary motions are important for generating natural motions like those of humans. Thus, we propose a natural behavior generation method for humanoid robots that is a hybrid generation between voluntary and involuntary motions. The key idea of our method is to control robots with a hybrid controller that combines the functions of a communication behavior controller and body balancing controllers. We also develop a wheeled inverted pendulum type of humanoid robot, named "Robovie-III," in order to generate involuntary motions like oscillation. This paper focuses on the system architecture of this robot. By applying our method to this robot and conducting preliminary experiments, we verify its validity. Experimental results show that the robot generates both voluntary and involuntary motions.

Background & Aims:The epidermal growth factor (EGF) receptor (EGFR) can be transactivated by many factors including G-protein-coupled receptor agonists and cytokines. Although this EGFR transactivation reportedly requires a disintegrin and metalloproteinase (ADAM) that sheds the ectodomain of EGFR ligands, the detailed mechanisms are still unknown. This study evaluated the mechanism of interleukin (IL)-8- and IL-1β-dependent shedding of the EGFR ligand in KATO III cells. Methods:We established transfectants stably expressing alkaline phosphatase-tagged heparin-binding EGF-like growth factor (HB-EGF), transforming growth factor α, or amphiregulin precursors, and depleted ADAM proteins, using short interfering RNA against ADAM10, 12, or 17. We assessed shedding of EGFR ligands by measuring AP activities in the conditioned media after IL-1β or IL-8 stimulation. EGFR activation was examined by immunoprecipitation and Western blotting using antiphosphotyrosine antibody. KB-R7785 and anti-IL-8 neutralizing antibody were used to inhibit activities of ADAMs and IL-8 action, respectively. Results:IL-8 dose dependently released the EGFR ligands and transiently phosphorylated EGFR, with a peak at 15 minutes. KB-R7785 completely blocked IL-8-induced shedding and EGFR transactivation. Depletion of ADAM10 also dramatically reduced IL-8-induced shedding and EGFR transactivation, but depletion of ADAM12 and 17 did not. IL-1β dose dependently enhanced shedding of HB-EGF, which was not blocked by KB-R7785 in the early phase. In the late phase, however, the EGFR transactivation was blocked by KB-R7785 and abrogated by anti-IL-8 neutralizing antibody. Conclusions:IL-8 induces shedding of EGFR ligands because of an ADAM10-dependent pathway in gastric cancer cells, whereas IL-1β acts principally by an ADAM-independent pathway. IL-1β-dependent prolonged EGFR transactivation involves multiple pathways, including an IL-8-dependent pathway.

Mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) gene are associated with chronic pancreatitis in Caucasians. We developed a simple method for measuring finger sweat chloride concentration to test whether CFTR dysfunction underlies chronic pancreatitis in Japan where cystic fibrosis (CF) is rare.

Ethanol is the leading cause of pancreatitis; however, its cellular effects are poorly understood. We examined the direct effects of ethanol in the concentration range 0.1‐30 mM, i.e. relevant to usual levels of drinking, on fluid secretion from guinea‐pig pancreatic duct cells. Fluid secretion was continuously measured by monitoring the luminal volume of interlobular duct segments isolated from the guinea‐pig pancreas. [Ca2+]iwas estimated by microfluorometry in duct cells loaded with fura‐2. Ethanol at 0.3‐30 mM significantly augmented fluid secretion stimulated by physiological (1 pM) or pharmacological (1 nM) concentrations of secretin. It augmented dibutyryl cAMP‐stimulated fluid secretion but failed to affect spontaneous or acethylcholine‐stimulated secretion. Ethanol at 1 mM shifted the secretin concentration‐fluid secretion response curve upwards and raised the maximal secretory response significantly by 41 %. In secretin‐stimulated ducts, 1 mM ethanol induced a transient increase in [Ca2+]ithat was dependent on the presence of extracellular Ca2+. Ethanol failed to augment secretin‐stimulated secretion from ducts pretreated with an intracellular Ca2+buffer (BAPTA) or a protein kinase A inhibitor (H89). In conclusion, low concentrations of ethanol directly augment pancreatic ductal fluid secretion stimulated by physiological and pharmacological concentrations of secretin, and this appears to be mediated by the activation of both the intracellular cAMP pathway and Ca2+mobilization.

Abstract.: Chronic pancreatitis is a continuing inflammatory disease characterized by irreversible morphological change and, typically, by pain and permanent impairment of function. The pathogenesis of pancreatitis, either acute or chronic, is still controversial. There have been no widely accepted concepts to provide a reasonable explanation linking the known etiological factors and the pathophysiological aspects of the disease. Alcohol is undoubtedly the major etiological factor in most countries, and the relative importance of alcohol as a cause of chronic pancreatitis ranges from 40% to 90% in various countries. As fewer than 10% of alcoholics develop chronic pancreatitis, other nutritional or genetic influences are likely to be involved in the pathogenesis of alcoholic pancreatitis. Accessory pancreas incidentally found in patients with chronic alcoholic pancreatitis does not always have the pathological findings seen in the main pancreas. Integrity of the pancreatic duct seems to be another important factor for chronic alcoholic pancreatitis. Gene mutations of the cystic fibrosis transmembrane conductance regulator (CFTR), cationic trypsinogen, and pancreatic secretory trypsin inhibitor have been investigated in idiopathic chronic pancreatitis. Molecular and cell biology research during the past few years has elucidated pathophysiological factors that are involved in the pathogenesis of chronic pancreatitis, but cannot demonstrate a common pathway between etiological factors and the pathogenesis or development of the disease.

The discovery of the gene for cystic fibrosis (CF), the cystic fibrosis transmembrane conductance regulator (CFTR), brought about a new era in the study of this disease. Identification of the molecular target has yielded a flood of data that add to our understanding of the pathogenesis, diagnosis and treatment of CF. The CFTR protein is a cAMP-regulated Cl−channel with multiple functions in epithelial cells. In the exocrine pancreas the CFTR plays a key role in the apical Cl−, HCO3−, and water transport in duct cells. The severe loss of functions, caused by mutations of the CFTR gene, leads to pathological lesions of the pancreas. Over 1200 CFTR mutations and polymorphisms have been identified and their diversity may explain the high level of heterogeneity in the CF phenotype. Mutation analyses of the CFTR gene have revealed a spectrum of CFTR-related diseases that do not fit the classical CF picture but are associated with dysfunction of CFTR, such as chronic pancreatitis.

A new “range-space” approach is described for synergistic resolution of both stereovision and reflectance (visual) modeling problems simultaneously. This synergistic approach can be applied to arbitrary camera arrangements with different intrinsic and extrinsic parameters, image types, image resolutions, and image number. These images are analyzed in a step-wise manner to extract 3-D range measurements and also to render a customized perspective view. The entire process is fully automatic. An extensive and detailed experimental validation phase supports the basic feasibility and generality of the Range-Space Approach.

This paper proposes aDistributed Vision System(DVS), which is an intelligent infrastructure for mobile robots consisting of manyvision agents(VAs) embedded in an environment. The system monitors the environment from various viewing points with the VAs, maintains the dynamic environment models, and provides various information to robots. Based on this concept, we have developed a prototype of the DVS which consists of sixteen vision agents and simultaneously navigates two robots in a model town.

Trypsinogen activation peptide (TAP) is a useful marker of severe acute pancreatitis. However, it is sometimes difficult to detect an elevation of plasma TAP in patients with acute pancreatitis because TAP is rapidly cleared from plasma. Therefore, urine TAP has been evaluated to provide an accurate prediction of the outcome of pancreatitis. In the present study, we examined the time course of plasma and urine TAP simultaneously after induction of taurocholate-induced pancreatitis in rats. Plasma TAP levels peaked at 1 hour after the induction of pancreatitis and then gradually decreased, but was still higher than prepancreatitis levels at 48 hours. Significant increases in urine TAP levels were seen at 0–6, 6–12, and 30–36 hours after induction of pancreatitis. The peak level of urine TAP output and TAP/creatinine ratio was observed at 6–12 and 30–36 hours, respectively. Urine TAP concentration showed a significant correlation with both urine TAP/creatinine ratio and TAP output in urine (p< 0.01). In conclusion, plasma TAP increased immediately after the induction of pancreatitis, but excretion of TAP into urine was delayed several hours in taurocholate-induced pancreatitis in rats. The measurement of urine TAP concentration alone sufficiently can reflect the amount of TAP liberated in the pancreas at initial stage of acute pancreatitis.

Long-term effects of nafamostat mesylate, a protease inhibitor, and imipenem, an antibiotic, on trypsin-taurocholate–induced acute pancreatitis were studied in rats. Sham-operated rats infused with a buffer solution into the pancreatic duct served as controls. Nafamostat (1 mg/kg), imipenem (10 mg/kg), or imipenem nafamostat in saline was injected subcutaneously 0.25, 3, 24, and 48 hours after the induction of pancreatitis. In untreated rats and control rats, saline was injected at the same intervals as in the treated rats. All rats in an untreated group died within 3.5 days (median survival, 1.25 day) after the induction of pancreatitis. The 2-week survival rate was significantly (p< 0.05) improved by a combination of nafamostat and imipenem (42), but not by nafamostat (17), or imipenem (8) alone. Bacterial culture at 24 hours revealed infection of necrotic pancreatic tissues and ascites by intestinal bacteria in all untreated rats but not in control rats. Bacterial counts were significantly reduced by imipenem, but not by nafamostat. In conclusion, bacterial infection occurred within 24 hours after the induction of trypsin-taurocholate pancreatitis in rats. Early treatment with nafamostat imipenem, but not nafamostat or imipenem alone, improves long-term survival.

Plasma and urine levels of trypsinogen activation peptides (TAP) reflect the severity of acute pancreatitis in experimental and clinical acute pancreatitis. In trypsin-taurocholate–induced pancreatitis in rats, the extrinsic bovine trypsin used for the induction of pancreatitis might influence on the TAP levels after induction of pancreatitis. The aim of the present study was to elucidate whether infused trypsin itself affects TAP levels in trypsin-taurocholate–induced pancreatitis. Rats were divided into three groups. In the pancreatitis group, acute pancreatitis was induced by a retrograde infusion of bovine trypsin and sodium taurocholate into the pancreatic duct. In the duct infusion group and peritoneal injection group, a mixture of bovine trypsin and trypsin inhibitor, ONO-3403, was infused into the pancreatic duct or the peritoneal cavity. Plasma and urine TAP concentration significantly increased in trypsin-taurocholate–induced pancreatitis but not in the duct infusion and peritoneal injection groups for 6 hours after the infusion of trypsin. Serum rat immunoreactive trypsin (IRT) and amylase significantly increased in the pancreatitis and duct infusion groups but not in the peritoneal injection group. Serum levels of bovine IRT in the pancreatitis group was significantly lower than those in duct infusion and peritoneal injection groups. In conclusion, an intraductal infusion of bovine trypsin itself into pancreatic duct does not influence the levels of plasma and urine TAP in trypsin-taurocholate–induced pancreatitis.

Ca2+/calmodulin-dependent protein (CaM) kinases play an important role in Ca2+-mediated secretory mechanisms. Previously, we demonstrated that a CaM kinase II inhibitor KN-62 had a small inhibitory effect on amylase secretion stimulated by CCK. In the present study, we investigated the effects of a myosin light chain kinase (MLCK) inhibitor on amylase secretion and Ca2+ signaling in rat pancreatic acini. A specific inhibitor of MLCK, wortmannin, inhibited amylase secretion stimulated by CCK-8 (30 pM) in a concentration-dependent manner. Wortmannin (10 μM) had no effects on basal secretion but reduced amylase secretion stimulated by CCK-8 (30 pM) by 67 ± 3%. Wortmannin inhibited amylase secretion stimulated by calcium ionophore (A23187) and phorbol ester (TPA). Wortmannin also inhibited amylase response to thapsigargin by 76 ± 8% and to both thapsigargin and TPA by 52 ± 10%. Ca2+ oscillations evoked by CCK-8 (10 pM) were inhibited by wortmannin (10 μM). Wortmannin had a little inhibitory effect on an initial rise in [Ca2+]i, and abolished a subsequent sustained elevation of [Ca2+]i evoked by 1 nM CCK-8. In conclusion, MLCK plays a crucial role in amylase secretion from pancreatic acini and regulates Ca2+ entry from the extracellular space.

High-affinity cholecystokinin (CCK) receptors were reported to be coupled with phospholipase A2(PLA2)-arachidonic acid (AA) pathways to mediate Ca2oscillations and amylase secretion in rat pancreatic acinar cells. To investigate which types of PLA2were involved in PLA2–AA pathways, the effects of specific inhibitors for type II and type IV PLA2on Ca2oscillations and amylase secretion were studied in isolated rat pancreatic acini. An inhibitor of type IV (cytosolic) PLA2, AACOCF3inhibited Ca2oscillations elicited by CCK-8 (30 p M) and JMV-180 (100 n M). AACOCF3inhibited amylase secretion stimulated by JMV-180 and low concentrations of CCK-8 (≤30 p M). On the other hand, an inhibitor of type II (secretory, nonpancreatic) PLA2had no effects on Ca2oscillations and amylase secretion stimulated by CCK-8 and JMV-180. These results suggest that high-affinity CCK receptors are coupled to cytosolic PLA2to mediate Ca2oscillations and amylase secretion in rat pancreatic acinar cells.