Momentum transport of morphological instability in fluid displacement with changes in viscosity.

Saffman-Taylor instability exhibits a stepwise unstable morphology from a stable interface to viscous fingering, eventually leading to tip splitting. The nonlinear dynamics of the destabilized interface depends on various flow properties. However, the physicochemical mechanism that determines the transition point of the flow state is unclear. We studied the interfacial instability transition in miscible displacement from a thermodynamic perspective by calculating the momentum transport and entropy production. Using numerical analysis based on Darcy's law coupled with the convection-diffusion equation, the observed flux-dependent flow state transitions were attributed to the selection of the flow state with a higher entropy production.

Comparison of clinical utility of deep learning-based systems for small-bowel capsule endoscopy reading.

BACKGROUND AND AIM: Convolutional neural network (CNN) systems that automatically detect abnormalities from small-bowel capsule endoscopy (SBCE) images are still experimental, and no studies have directly compared the clinical usefulness of different systems. We compared endoscopist readings using an existing and a novel CNN system in a real-world SBCE setting. METHODS: Thirty-six complete SBCE videos, including 43 abnormal lesions (18 mucosal breaks, 8 angioectasia, and 17 protruding lesions), were retrospectively prepared. Three reading processes were compared: (A) endoscopist readings without CNN screening, (B) endoscopist readings after an existing CNN screening, and (C) endoscopist readings after a novel CNN screening. RESULTS: The mean number of small-bowel images was 14 747 per patient. Among these images, existing and novel CNN systems automatically captured 24.3% and 9.4% of the images, respectively. In this process, both systems extracted all 43 abnormal lesions. Next, we focused on the clinical usefulness. The detection rates of abnormalities by trainee endoscopists were not significantly different across the three processes: A, 77%; B, 67%; and C, 79%. The mean reading time of the trainees was the shortest during process C (10.1 min per patient), followed by processes B (23.1 min per patient) and A (33.6 min per patient). The mean psychological stress score while reading videos (scale, 1-5) was the lowest in process C (1.8) but was not significantly different between processes B (2.8) and A (3.2). CONCLUSIONS: Our novel CNN system significantly reduced endoscopist reading time and psychological stress while maintaining the detectability of abnormalities. CNN performance directly affects clinical utility and should be carefully assessed.

Experimental demonstration of the suppression of viscous fingering in a partially miscible system.

Phase separation is ubiquitous in nature and technology. So far, the focus has primarily been on phase separation occurring in the bulk phase. Recently, phase separation taking place in interfacial areas has attracted more attention - in particular, a combination of interfacial phase separation and hydrodynamics. Studies on this combination have been conducted intensively in this past decade; however, the detailed dynamics remain unclear. Here, we perform fluid displacement experiments, where a less viscous solution displaces a more viscous one in a radially confined geometry and phase separation occurs at the interfacial region. We demonstrate that a finger-like pattern, due to the viscosity contrast during the displacement, can be suppressed by the phase separation. We also claim that the direction of a body force, the so-called Korteweg force, which appears during the phase separation and induces convection, determines whether the fingering pattern is suppressed or changed to a droplet pattern. The change of the fingering pattern to the droplet pattern is enhanced by the Korteweg force directed from the less viscous solution to the more viscous one, whereas the fingering is suppressed by the force directed in the opposite direction. These findings will contribute directly to the higher efficiency of processes such as enhanced oil recovery and CO2 sequestration, where interfacial phase separation is considered to occur during the flow.

Unpredictable polymeric flow dynamics with reaction between HPAM and Al3+ by comparison between pre- and post-reaction fluid properties.

A chemical reaction in the flow field affects the physical property of fluids, resulting in changing flow dynamics. The effect of the reaction on the flow dynamics is normally evaluated by comparison between the physical properties of the fluid between pre- and post-reaction. However, our group found a polymeric reacting flow in which a comparison between pre- and post-reaction fluid properties is insufficient to evaluate the influences of the reaction on the flow dynamics (T. Ueki et al., J. Phys. Chem. B, 2019, 123, 4587-4593). In the study, we examined the stirred flow by an impeller in a beaker with a chemical reaction between partially hydrolyzed polyacrylamide (HPAM) solution and Fe(NO3)3 solution. We found that a so-called Weissenberg effect, where the stirred solution climbs up the stirring shaft because of an increase in the viscoelasticity of the mixed solution, transiently appeared in only the halfway of the reaction, although the reaction slightly decreased the solution's viscosity at the final stage under a certain pH and we proposed the mechanism for the temporal increase in the viscoelasticity. In the present study, we conducted similar experiments as our previous study using HPAM solution at various pH and two concentrations of Al(NO3)3 solutions. The unpredictable flow dynamics by comparison between pre- and post-reaction fluid properties, i.e., the appearance and disappearance of the Weissenberg effect, has been observed under a certain pH and Al(NO3)3 concentration. We investigated the mechanism by means of the simultaneous measurement of pH and the stirring torque and the identification of the dominant species of aluminum aqua complexes by the Henderson-Hasselbalch equation. As a result, we proposed two mechanisms of dissapearance of the Weissenberg effect: one is the same for the Fe(NO3)3 case but the other is unique and novel for the Al(NO3)3 case. This study can contribute to the comprehensive understanding of the conditions for the occurrence of the unpredictable dynamics of polymeric reacting flow by comparison between the pre- and post-reaction fluid properties.

Structural and Chemical Effects of the Surrounding Cations and Coexisting Compounds on [M(α-PW11O39)2]n.

The effects of countercations and coexisting compounds on the molecular structure of the [M(α-PW11O39)2] n- polyanion were analyzed in terms of the repulsion and twisting of two [α-PW11O39]7- units. More specifically, it was found that two [α-PW11O39]7- ions approached one another upon reducing the ionic radius of M in [M(α-PW11O39)2] n-. The interactive twisting of the [α-PW11O39]7- units prevented mutual repulsion of the units containing terminal O atoms, and the tendency for approach and twisting of the [α-PW11O39]7- units varied as a function of the type of countercation and the presence of coexisting compounds. Overall, this study demonstrated that some interactions between the counteraction and coexisting compounds with [M(α-PW11O39)2] n- determined the molecular conformation and the isolated form of the polyanion.

Periodontopathic Bacterium Fusobacterium nucleatum Affects Matrix Metalloproteinase-9 Expression in Human Alveolar Epithelial Cells and Mouse Lung.

BACKGROUND/AIM: Despite evidence of an association between pulmonary diseases and periodontopathic bacteria, the molecular mechanisms remain unknown. Matrix metalloproteinase-9 (MMP9) plays important roles in pneumonia, chronic obstructive pulmonary disease, and asthma; therefore, we assessed the effects of Fusobacterium nucleatum on MMP9 expression in mouse lung and A549 human alveolar epithelial cells. MATERIALS AND METHODS: Heat-killed F. nucleatum was administered to the trachea of mice or added to A549 cell cultures. MMP9 expression was determined using real-time PCR and western blotting. The involvement of mitogen-activated protein kinases (MAPKs) and nuclear factor-κB (NF-κB) in MMP9 expression was examined. RESULTS: F. nucleatum induced expression of MMP9 in mouse lung and bronchoalveolar lavage fluid. In A549 cells, F. nucleatum induced production of MMP9 protein and mRNA in a density-dependent manner; this was inhibited by inhibitors of extracellular-regulated kinase 1/2 and NF-κB, but not of p38 and Jun N-terminal protein kinase. CONCLUSION: F. nucleatum may contribute to the onset of pulmonary diseases via MMP9 expression through extracellular-regulated kinase 1/2 and NF-κB activation.

Fusobacterium nucleatum exacerbates chronic obstructive pulmonary disease in elastase-induced emphysematous mice.

Exacerbation of chronic obstructive pulmonary disease (COPD) is associated with disease progression and increased mortality. Periodontal disease is a risk factor for exacerbation of COPD, but little is known about the role of periodontopathic bacteria in this process. Here, we investigated the effects of intratracheal administration of Fusobacterium nucleatum, a periodontopathic bacteria species, on COPD exacerbation in elastase-induced emphysematous mice. The administration of F. nucleatum to elastase-treated mice enhanced inflammatory responses, production of alveolar wall destruction factors, progression of emphysema, and recruitment of mucin, all of which are symptoms observed in patients with COPD exacerbation. Hence, we propose that F. nucleatum may play a role in exacerbation of COPD.

Growing Interface with Phase Separation and Spontaneous Convection during Hydrodynamically Stable Displacement.

The displacement of one fluid by another is an important process, not only in industrial and environmental fields, such as chromatography, enhanced oil recovery, and CO2 sequestration, but also material processing, such as Lost Foam Casting. Even during hydrodynamically stable fluid displacement where a more viscous fluid displaces a less viscous fluid in porous media or in Hele-Shaw cells, the growing interface fluctuates slightly. This fluctuation is attributed to thermodynamic conditions, which can be categorized as the following systems: fully miscible, partially miscible, and immiscible. The dynamics of these three systems differ significantly. Here, we analyze interfacial fluctuations under the three systems using Family-Vicsek scaling and calculate the scaling indexes. We discovered that the roughness exponent, α, and growth exponent, ß, of the partially miscible case are larger than those of the immiscible and fully miscible cases due to the effects of the Korteweg convection as induced during phase separation. Moreover, it is confirmed that fluctuations in all systems with steady values of α and ß are represented as a single curve, which implies that accurate predictions for the growing interface with fluctuations in Hele-Shaw flows can be accomplished at any scale and time, regardless of the miscibility conditions.

Tunable Hydrodynamic Interfacial Instability by Controlling a Thermodynamic Parameter of Liquid-Liquid Phase Separation.

Herein, we report on the hydrodynamic interfacial instability controlled by a thermodynamic parameter driving the liquid-liquid phase separation during fluid displacement in a Hele-Shaw cell. This instability remains even when the solution is guaranteed to be hydrodynamically stable. Adjusting the salt concentration helps control the miscibility of the solutions and change the pattern of the interface. We observe stable circular, fingering, and droplet formation patterns as the salt concentration is decreased from equilibrium. In addition, we analyze this interfacial instability using thermodynamic flux, which is determined from the growth rate of the interface, and provide a theoretical framework to quantitatively predict the transition points between the patterns. We find that the patterns transition to a state having higher entropy production.

Anomalous patterns of Saffman-Taylor fingering instability during a metastable phase separation.

Phase separation is important in biology, biochemistry, industry, and other areas and is divided into two types: a spinodal decomposition type and a nucleation and growth type. The spinodal decomposition type phase separation occurs under the thermodynamically unstable conditions, and the nucleation and growth type phase separation occurs under thermodynamically metastable conditions. On the other hand, when a less viscous fluid displaces a more viscous one in porous media, the interface of the two fluids becomes hydrodynamically unstable and forms a finger-like pattern. The coupling of the hydrodynamic instability with the thermodynamic instability has been studied. It is reported that the hydrodynamic instability under thermodynamically unstable conditions, where spinodal decomposition type phase separation occurs, creates multiple moving droplets with a radius of 3-4 mm because of the spontaneous convection induced by the Korteweg force, which is driven by a compositional gradient during phase separation. However, the hydrodynamic instability under metastable conditions, where the phase separation of nucleation and growth type occurs, is still unrevealed. In this study, we applied fingering instability (hydrodynamic instability) under the metastable conditions, where the patterns are changed from fingering or droplets to anomalous patterns such as tip-widening or needle-like (top-pointed) fingering patterns when the initial concentration is metastable, which is considered near a binodal curve. These patterns are ubiquitous in nature, similar to dendrite crystals (snowflakes) or our body's cells. Thus, the patterns created can be controlled through hydrodynamic conditions such as the injection flow and thermodynamic conditions such as spinodal decomposition (thermodynamically unstable conditions) and metastable conditions.

Expression of the SARS-CoV-2 Receptor ACE2 and Proinflammatory Cytokines Induced by the Periodontopathic Bacterium Fusobacterium nucleatum in Human Respiratory Epithelial Cells.

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is currently a global public health emergency. Periodontitis, the most prevalent disease that leads to tooth loss, is caused by infection by periodontopathic bacteria. Periodontitis is also a risk factor for pneumonia and the exacerbation of chronic obstructive pulmonary disease, presumably because of the aspiration of saliva contaminated with periodontopathic bacteria into the lower respiratory tract. Patients with these diseases have increased rates of COVID-19 aggravation and mortality. Because periodontopathic bacteria have been isolated from the bronchoalveolar lavage fluid of patients with COVID-19, periodontitis may be a risk factor for COVID-19 aggravation. However, the molecular links between periodontitis and COVID-19 have not been clarified. In this study, we found that the culture supernatant of the periodontopathic bacterium Fusobacterium nucleatum (CSF) upregulated the SARS-CoV-2 receptor angiotensin-converting enzyme 2 in A549 alveolar epithelial cells. In addition, CSF induced interleukin (IL)-6 and IL-8 production by both A549 and primary alveolar epithelial cells. CSF also strongly induced IL-6 and IL-8 expression by BEAS-2B bronchial epithelial cells and Detroit 562 pharyngeal epithelial cells. These results suggest that when patients with mild COVID-19 frequently aspirate periodontopathic bacteria, SARS-CoV-2 infection is promoted, and inflammation in the lower respiratory tract may become severe in the presence of viral pneumonia.

Porphyromonas gingivalis gingipains potentially affect MUC5AC gene expression and protein levels in respiratory epithelial cells.

Porphyromonas gingivalis (Pg) is a periodontopathic pathogen that may affect MUC5AC-related mucus hypersecretion along airway epithelial cells. Here, we attempted to establish whether Pg virulence factors (lipopolysaccharide, FimA fimbriae, gingipains) affect MUC5AC in immortalized and primary bronchial cells. We report that MUC5AC gene expression and protein levels are affected by Pg culture supernatant, but not by lipopolysaccharide or FimA fimbriae. Cells treated with either Pg single (Kgp or Rgp) or double (Kgp/Rgp) mutants had altered levels of MUC5AC gene expression and protein levels, and MUC5AC staining of double mutant-treated mouse lung cells showed that MUC5AC protein levels were unaffected. Taken together, we propose that Pg gingipains may be the primary virulence factor that influences both MUC5AC gene expression and protein levels.

Gene Expression and Histochemical Analyses in the Fatty Livers of Rats Fed a Histidine-Excess Diet.

Triglyceride (TG) and cholesterol accumulation are known to occur in the liver of rats fed a histidine-excess (5%) diet, but there are few studies reporting histochemical and molecular biological analyses of the rat liver. The aim of this study was to elucidate the molecular basis of this lipid-accumulation mechanism. Lipid accumulations, tissue section images, and gene expression levels were compared in the livers of rats fed a control or histidine-excess diet for 5 wk (n=8/group). Serum levels of TGs, free fatty acids, total cholesterol, high-density lipoprotein cholesterol, glucose, albumin, and the enzyme activities of aspartate aminotransferase and alanine aminotransferase were also analyzed. In the livers of rats fed a histidine-excess diet, histochemical analyses showed what appeared to be a preliminary stage of nonalcoholic fatty liver, characterized by lipid accumulation around the central vein area and minor fibrosis. However, there were no changes in serum TG or free fatty acid levels. Quantitative PCR analyses showed the up-regulation of FAT/CD36, which is related to the uptake of fatty acids into cells, and the downregulation of two apolipoprotein genes, ApoC3 and ApoE. The mRNA levels of PPARγ, LXRα, and AMPKα in the liver were also reduced by excess histidine intake. The results of this study suggest that steatosis caused by excess histidine intake may be the result of an imbalance between lipid transport from the liver and the uptake of free fatty acids into hepatocytes.

Weaning from long-term mechanical ventilation utilizing closed-loop ventilation mode (IntelliVent®-ASV®) in a patient with spinal cord injury.

INTRODUCTION: Cervical spinal cord injury with the C3 neurological level may cause respiratory failure and require long-term mechanical ventilation. Conventional weaning of spontaneous breathing trials is difficult to perform outside of intensive care or spinal cord units. CASE PRESENTATION: An 80-year-old man presented with total tetraplegia and restrictive respiratory failure that required assisted ventilation after a falling accident. Cervical spine magnetic resonance imaging showed cervical cord compression that was worst at the C3-C4 intervertebral level. He experienced unexpected cardiac arrest during the conventional weaning process of trials of intermittent spontaneous breathing in the intensive care unit. The automated weaning protocol utilizing a closed-loop ventilation mode (IntelliVent®-ASV ® ) was introduced 131 days after injury in our ward for chronically ill patients. The patient was successfully weaned 39 days after the introduction of the weaning protocol. DISCUSSION: An automated weaning protocol utilizing a closed-loop ventilation mode could be an optional procedure in patients with cervical cord injury on long-term mechanical ventilation, even in a ward for chronically ill patients where sufficient staff is not available. The efficacy and safety, and the cost-effectiveness of the procedure should be examined in larger spinal cord units.

Low-Dose Sodium Nitrite Fluid Resuscitation Prevents Lethality From Crush Syndrome by Improving Nitric Oxide Consumption and Preventing Myoglobin Cytotoxicity in Kidney in A Rat Model.

OBJECTIVE: Crush syndrome (CS) is a serious medical condition characterized by muscle cell damage resulting from pressure. CS has a high mortality, even when patients receive fluid therapy. We examined whether administration of NaNO2-containing fluid can improve survival in a rat model of CS. DESIGN: The CS model was generated by subjecting anesthetized rats to bilateral hind limb compression with a rubber tourniquet for 5 h. Rats were then randomly divided into six groups: sham; CS with no treatment; CS with normal saline treatment; CS with normal saline + 25 mEq/L bicarbonate treatment; and CS with normal saline + 200 or 500 µmol/kg NaNO2. MEASUREMENTS AND MAIN RESULTS: Blood and tissue samples were collected for histological and biochemical analyses at predetermined time points before and after reperfusion. Ischemic compression of rat hind limbs reduced nitrite content in the crushed muscle, and subsequent reperfusion resulted in reactive oxygen species-induced circulatory dysfunction and systemic inflammation. Rats treated with 200 µmol/kg NaNO2 showed increased nitric oxide (NO) levels, blood circulation, and neoangiogenesis, decreased generation of reactive oxygen species, and suppression of the inflammatory response, leading to complete recovery. CONCLUSIONS: Treatment with 200 µmol/kg NaNO2 prevents muscle damage induced by ischemia reperfusion via the protective effects of NO and suppression of systemic inflammation, thereby increasing survival rates in CS.

Determination and Identification of a Specific Marker Compound for Discriminating Shrub Chaste Tree Fruit from Agnus Castus Fruit Based on LC/MS Metabolic Analysis.

Shrub Chaste Tree Fruit (SCTF) is defined as the fruits of Vitex rotundifolia L. f. and V. trifolia L. and has been used as a component of some traditional Japanese medicines (Kampo formulations). Agnus Castus Fruit (ACF) is defined as the dried ripe fruits of V. agnus-castus L.; it is used in traditional European medicines, but is becoming popular in Japan as both an over-the-counter drug and as an ingredient in health foods for treating premenstrual syndrome (PMS). To ensure the efficacy and safety of both SCTF and ACF products, it is important to precisely authenticate their botanical origins and to clearly distinguish between SCTF and ACF. Therefore, we tried to identify SCTF-specific marker compounds based on LC/MS metabolic analysis. The multivariate analysis of LC/MS data from SCTF and ACF samples furnished candidate marker compounds of SCTF. An SCTF-specific marker was isolated from SCTF crude drugs and identified as 3-O-trans-feruloyl tormentic acid on the basis of spectroscopic data from NMR and MS. Since avoiding contamination from closely related species is a significant requirement for pharmaceuticals of natural origin, this information will be valuable for the quality control of both SCTF and ACF products from the viewpoint of regulatory science.

Identification of New Diterpenes as Putative Marker Compounds Distinguishing Agnus Castus Fruit (Chaste Tree) from Shrub Chaste Tree Fruit (Viticis Fructus).

Agnus Castus Fruit is defined in the European Pharmacopoeia as the dried ripe fruit of Vitex agnus-castus. In Europe it is used as a medicine targeting premenstrual syndrome and climacteric disorder. In Japan, Agnus Castus Fruit is becoming popular as a raw material for over-the-counter drugs and health food products, though its congenic species, Vitex rotundifolia and Vitex trifolia, have been used as Shrub Chaste Tree Fruit in traditional medicines. Therefore, it is important to discriminate these Vitex plants from the viewpoint of regulatory science. Here we tried to identify putative marker compounds that distinguish between Agnus Castus Fruit and Shrub Chaste Tree Fruit. We analyzed extracts of each crude drug by liquid chromatography-mass spectrometry, and performed differential analysis by comparison of each chromatogram to find one or more peaks characteristic of Agnus Castus Fruit. A peak was isolated and identified as an equilibrium mixture of new compounds named chastol (1) and epichastol (1a). The planar structures of 1 and 1a were determined spectroscopically. Their relative configurations were revealed by nuclear Overhauser effect spectroscopy and differential nuclear Overhauser effect-NMR data. Since avoiding contamination from closely related species is needed for the quality control of natural pharmaceuticals, this information will be valuable to establish a method for the quality control of both, Agnus Castus Fruit and Shrub Chaste Tree Fruit products.

Sinodielide A exerts thermosensitizing effects and induces apoptosis and G2/M cell cycle arrest in DU145 human prostate cancer cells via the Ras/Raf/MAPK and PI3K/Akt signaling pathways.

Sinodielide A (SA) is a naturally occurring guaianolide, which is isolated from the root of Sinodielsia yunnanensis. This root, commonly found in Yunnan province, is used in traditional Chinese medicine as an antipyretic, analgesic and diaphoretic agent. A number of studies have reported that agents isolated from a species of Umbelliferae (Apiaceae) have antitumor activities. We previously reported, using combined treatments with this medicinal herb and hyperthermia at various temperatures, an enhanced cytotoxicity in the human prostate cancer androgen­independent cell lines, PC3 and DU145, and analyzed the related mechanisms. In the present study, we investigated the effects of treatment with SA prior to hyperthermia on the thermosensitivity of DU145 cells, and the mechanisms related to the induction of apoptosis and G(2)/M cell cycle arrest via the activation of extracellular-regulated kinase (ERK)1/2, c-Jun N-terminal kinase (JNK) mitogen-activated protein kinase (MAPK) signaling pathways, as well as the phosphoinositide 3-kinase (PI3K)/Akt signaling pathways. Cells were exposed to hyperthermia alone (40-44˚C) or hyperthermia in combination with SA. Lethal damage to cells treated with mild hyperthermia (40 or 42˚C) for up to 6 h was slight; however, hyperthermia in combination with SA synergistically enhanced thermosensivity. Lethal damage to cells treated with acute hyperthermia (43 or 44˚C) was more severe, but these effects were also enhanced and were more significant by the combined treatment with SA. The kinetics of apoptosis induction and cell cycle distribution were analyzed by flow cytometry. In addition, the levels of ERK1/2, JNK and Akt were determined by western blot analysis. The incidence of apoptotic cells after treatment with SA (20.0 µM) at 37˚C for 4 h, hyperthermia (44˚C) alone for 30 min, and the combination in sequence were examined. The sub-G1 division (%) in the diagram obtained by flow cytometry was applied to that assay. The percentage of apoptotic cells (10.53±5.02%) was higher at 48 h as compared to 0, 12 and 24 h after treatment. The distribution of DU145 cells in the G2/M cell cycle phase was markedly increased after 24 h of heating at 44˚C and after the combined treatment with heating and SA. The phosphorylation of ERK1/2 was reduced following treatment with heating and SA, while the levels of phosphorylated JNK (p-JNK) were markedly increased immediately after heating at 44˚C and when heating was combined with SA. By contrast, the levels of phosphorylated Akt (p-Akt) were immediately increased only after heating at 44˚C. Thus, we concluded that SA exerts its thermosensitizing effects on DU145 cells by inhibiting the activation of the MAPK/ERK1/2 and PI3K/Akt signaling pathways.

Optical precursors in coupled-resonator-induced transparency.

We experimentally examined the propagation of temporally square modulated optical pulses through a coupled ring resonator. Sharp transient spikes appeared as the square pulses entered the system. The main signal gradually grew up through coupled-resonator-induced transparency (CRIT), with the time constant determined by a second resonator. Transient spikes were attributed to the higher and lower spectral components of the incident pulse, to which the resonators cannot respond; hence, they were interpreted as optical precursors. The experiments, therefore, demonstrated that precursors and the main signal can be observed separately, with amplitudes comparable to that of the incident step in CRIT.

VIP and calcitonin-producing pancreatic neuroendocrine tumor with watery diarrhea: clinicopathological features and the effect of somatostatin analogue.

CONTEXT: Pancreatic neuroendocrine tumor (pNET) secretes various peptide hormones; however, calcitonin hypersecretion is rare. Its clinicopathological significance and treatment is still controversial. CASE REPORT: A 43 year-old Japanese man presented severe watery diarrhea and a large mass in the pancreatic tail. Blood concentration of VIP was elevated to 649 pg/mL (reference range: 0-100 pg/mL), and calcitonin to 66,700 pg/mL (reference range: 15-86 pg/mL). There was no tumor in other endocrine organs. The resected tumor was composed of 80% calcitonin-positive cells and 10% VIP-positive cells. After the operation, the levels of VIP and calcitonin were decreased to 44 and 553 pg/mL, respectively, and diarrhea was improved. The mRNA of somatostatin receptor (SSTR) subtypes 2, 3 and 5 in the tumor tissue were increased 22.8, 25.1, and 37.0-fold of those of normal pancreas, respectively. At 19 months after the operation, blood calcitonin was again raised to 3,980 pg/mL, and metastatic tumors were found in the liver. With the treatment of long-acting somatostatin analogue, calcitonin was reduced to 803 pg/mL. The patient does not present endocrine symptom, and the size of the metastatic tumors appears stable. CONCLUSION: From the world literature to date, co-secretion of VIP and calcitonin was documented in only 10 cases of pNET including the current case. Although VIP is a primary cause of diarrhea in these cases, high level of calcitonin may also influence on the clinical symptoms. Somatostatin analogue suppresses the levels of VIP and calcitonin, and the control proliferation is also expected when tumor cells express SSTRs.