2. VIP (10-11-10-' M) had no effect on the resting membrane potential or on the input resistance of the smooth muscle cells of dog and cat trachea. However, with increased concentrations (> 10-8 M) VIP hyperpolarized the membrane and decreased the input resistance of the membrane in both tissues.3. VIP (1O-10-1O-7 M) dose-dependently reduced the amplitude of the contractions evoked through the nervous structure excited by field stimulation in the combined presence of indomethacin (10-5 M) and guanethidine (106 M) in the dog, and in the presence of guanethidine (10-6 M) in cat trachea. In parallel with actions on twitch contractions, VIP (1011 -10-7 M) reduced the amplitude of the excitatory junction potentials (EJPs) evoked through the nervous structure excited by single pulse field stimulation in both tissues. 4. VIP (10" M) had no effect on the post-junctional response of smooth muscle cells to exogenous acetylcholine (ACh) (10-9-10-5 M).5. During repetitive field stimulation at the stimulus frequency of 0-033-01 Hz, the amplitude of the EJPs was gradually reduced, and VIP (10-1 M) enhanced this depression phenomenon in the dog and cat trachea. 6. EJPs also showed summation when repetitive field stimulation was applied at high frequency (20 Hz) in the dog trachea. The slope of the relationship between the relative amplitude of the EJP and number of stimuli at 20 Hz was 2-2 + 0-4 mV/ stimulation (n = 4) in the dog trachea. However, in the cat trachea, summation of EJPs was not prominent, giving a mean slope of 0-6 + 0-2 mV/stimulation (n = 6) measured by the microelectrode method. VIP (10-M) shifted downward the relationship between the relative amplitude of the EJP and the number of stimuli at 20 Hz in both tissues.7. Overnight incubation with VIP antiserum (106 g/ml) had little effect on the depression of the EJP in the dog and cat trachea, or the summation of the EJP MS 8074 RH. HAKODIA AAND Y. ITO observed in the dog trachea. However, this procedure enhanced the summation of EJPs observed in the cat trachea, and the mean slope of the relationship between relative amplitude of the EJP and number of stimuli at 20 Hz was increased from 06+02 mV/stimulation (n = 6) to 1-5+0-1 mV/stimulation (n = 5) when the microelectrode method was employed.8. Overnight incubation of the cat tracheal tissue with VIP antiserum markedly reduced the amplitude of the muscle relaxation evoked by electrical field stimulation during contraction induced by 5-hydroxytryptamine (10' M) in the presence of atropine (10-6 M) and guanethidine (106 m 11. These results indicate that VIP in low concentrations has a prejunctional action inhibiting the excitatory neuroeffector transmission in addition to a direct action on the smooth muscle cells, presumably by suppressing transmitter release from the vagus nerves in dog and cat trachea. Furthermore in the cat trachea, the effects of VIP antiserum and VIP antagonists suggest that VIP may contribute to non-adrenergic non-cholinergic inhibitory responses and the endogenous VIP also inhibits A...

1 Tissue taken at operation was used to study the electrical and mechanical properties of human bronchial smooth muscle with intracellular microelectrodes and isometric recording of tension changes. 2 Over 90% of the muscle strips exhibited spontaneous tone and 70% produced spontaneous phasic contractions. The resting membrane potential of the smooth muscle cells ranged between -40 to -50 mV with a mean value of -44.9 + 5.2 mV (n = 92 ± s.d.). Spontaneous oscillations of the membrane potential (slow waves) were observed in 90% of the cells examined. 3 The electrical slow waves, phasic contractions and spontaneous tone were greatly reduced by

SUMMARY1. The effects of epithelial cells were investigated on resting membrane potential and neuro-effector transmission in smooth muscle cells of the dog tracheal and bronchiolar tissues.2. The mean value of the resting membrane potential of the epithelium-intact bronchiolar smooth muscle cells of the dog was -700 + 1 mV (± S.D., n = 40) and mechanical denudation of the epithelial layer depolarized the membrane to -57 0 + 2'5 mV (± S.D., n = 40). Application of isolated and dispersed epithelial cells (> 2 x 105 cells/ml) to the perfusing solution repolarized the membrane of epithelium-denuded bronchiolar smooth muscle cells to -670 + 2-7 mV (± S.D., n = 20).The mean resting membrane potential of the mucosa-free tracheal smooth muscle cells was -59-1 + 1-4 mV (± S.D., n = 50), and application of isolated and dispersed cells (> 2 x 105 cells/ml) hyperpolarized the membrane to -67-2 + 1'8 mV (± S.D., n = 50). These repolarizing actions were not modified by indomethacin (10-5 M).3. In the epithelium-denuded bronchioles, ACh (> 10-9 M) dose-dependently depolarized the smooth muscle cells, while in the epithelium-intact bronchioles, ACh (10-11-10-8 M) did not affect the resting membrane potential. At a concentration of 10-7 M, ACh significantly depolarized the membrane.4. Electrical field stimulation (EFS; 50,ts in duration and about 10-20 V in strength) applied to ring preparations of the bronchioles evoked twitch-like contractions (hereafter referred as twitch contraction), and size of the twitch contractions gradually and continuously decreased in the presence or absence of indomethacin (10-5 M) and guanethidine (10-6 M). When similar experiments were performed using epithelium-denuded bronchiolar ring preparations, in no case was there a prominent reduction in the amplitude of the twitch contractions in the presence of indomethacin and guanethidine.5. The decremental response of the twitch contraction observed in the epitheliumintact bronchioles was overcome by application of the leukotriene synthesis inhibitor AA861 (10-6 M) and the leukotriene antagonist ON01078 (10-5 M).6. Leukotrienes C4 and D4 (LTC4 and LTD4, > 10-8 M) evoked muscle contraction with a steady increase in muscle tone, up to a certain level. However, at 10-9 M, LTC4 increased and LTD4 decreased the amplitude of the twitch contractions evoked by MS 9432

Background Probe electrospray ionization-mass spectrometry (PESI-MS) can rapidly visualize mass spectra of small, surgically obtained tissue samples, and is a promising novel diagnostic tool when combined with machine learning which discriminates malignant spectrum patterns from others. The present study was performed to evaluate the utility of this device for rapid diagnosis of colorectal liver metastasis (CRLM). Methods A prospectively planned study using retrospectively obtained tissues was performed. In total, 103 CRLM samples and 80 non-cancer liver tissues cut from surgically extracted specimens were analyzed using PESI-MS. Mass spectra obtained by PESI-MS were classified into cancer or non-cancer groups by using logistic regression, a kind of machine learning. Next, to identify the exact molecules responsible for the difference between CRLM and non-cancerous tissues, we performed liquid chromatography-electrospray ionization-MS (LC-ESI-MS), which visualizes sample molecular composition in more detail. Results This diagnostic system distinguished CRLM from non-cancer liver parenchyma with an accuracy rate of 99.5%. The area under the receiver operating characteristic curve reached 0.9999. LC-ESI-MS analysis showed higher ion intensities of phosphatidylcholine and phosphatidylethanolamine in CRLM than in non-cancer liver parenchyma (P < 0.01, respectively). The proportion of phospholipids categorized as monounsaturated fatty acids was higher in CRLM (37.2%) than in non-cancer liver parenchyma (10.7%; P < 0.01). Conclusion The combination of PESI-MS and machine learning distinguished CRLM from non-cancer tissue with high accuracy. Phospholipids categorized as monounsaturated fatty acids contributed to the difference between CRLM and normal parenchyma and might also be a useful diagnostic biomarker and therapeutic target for CRLM.

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BackgroundRecently, gastrointestinal stromal tumors that have developed outside of the digestive tract have been reported. These tumors are collectively termed extra-gastrointestinal stromal tumors. Extra-gastrointestinal stromal tumors can also develop in the liver. Only eight case reports involving primary GIST of the liver have been published. We report a case and review the literature regarding this disease.Case presentationA 70-year-old woman with a past history of gastric cancer visited our hospital for regular inspection. With extensive radiological imaging, a computed tomography scan revealed a mass with a size of 6.8 cm in the lateral segment of the liver. 18F-Fluoro-2-deoxyglucose positron emission tomography revealed no other malignancies except for the liver tumor. Because the lesion was suspected of being a primary malignant hepatic tumor, lateral segmentectomy was performed. The immunohistochemical analysis supported the diagnosis of gastrointestinal stromal tumors in the liver. The patient has had no evidence of recurrence during the 10-month follow-up period; imatinib chemotherapy was not administered.ConclusionsPrimary hepatic gastrointestinal stromal tumors had no characteristics that distinguished them from ordinary tumors in imaging examinations. Primary gastrointestinal stromal tumors might have developed from interstitial Cajal-like cells.

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BackgroundLarger insulinomas are reportedly more likely to be malignant; however, their biological behavior has not been clearly elucidated. We here report the characteristics and treatment of a giant insulinoma with local invasion and lymph node metastasis. We also review published reports concerning the clinical features of giant insulinomas and comparing their grading with that of pancreatic neuroendocrine tumors.Case presentationA 71-year-old man was referred to our hospital for investigation of persistent hypoglycemia. On the current presentation, laboratory tests showed serum glucose, immunoreactive insulin, and C peptide concentrations of 45 mg/dL, 17.2 μIU/mL and 4.1 ng/mL, respectively. Dynamic magnetic resonance imaging showed a hypervascular tumor measuring 13.5 cm in the head of the pancreas. Computed tomography scanning demonstrated local invasion and lymph node involvement. He thus had Whipple’s triad, which is associated with malignant insulinoma. No distant metastases having been identified, pancreaticoduodenectomy was performed. Intraoperatively, three separate tumors were identified in the pancreatic head. Pathological examination showed all three tumors were pancreatic neuroendocrine tumors; the tumor cells in the largest mass were strongly immunoreactive for insulin. The Ki-67 index was 2–5% in most parts of the largest tumor and over 20% in the poorly differentiated areas. This tumor was classified as neuroendocrine carcinoma in accordance with the 2010 World Health Organization classification of pancreatic endocrine neoplasms. He remains free of evidence of recurrence 2 years postsurgery.A review of published reports indicated that giant insulinomas are more malignant than smaller ones, and metastatic disease is found on presentation in 56% of patients with giant insulinomas; however, we were unable to identify any correlation between grade of pancreatic neuroendocrine tumor and biological behavior of giant insulinomas.ConclusionsGiant insulinomas more frequently exhibit malignant behavior, such as local invasion, lymph node involvement, and liver metastasis, than smaller ones. However, there was no relationship between grade and rate of metastases or survival in this small case series. Identification of useful biological markers is necessary.