Mechanism of inhibitory effect of glucagon on gastrointestinal motility and cause of side effects of glucagon

Glucagon is commonly used during gastrointestinal examinations for the temporary inhibition of gastroduodenal movements. Three preparations of glucagon are now clinically available: those prepared by extraction from the pancreas (GL-P), by chemical synthesis (GL-S), and by genetic recombination (GL-G). The aim of this study was examine the mechanism of the inhibitory effect of glucagon on gastrointestinal motility and the cause of its side effects by comparing three glucagon preparations. In four conscious dogs, gastrointestinal contractions were monitored by means of chronically implanted force transducers. Each glucagon preparation (GL-P [15 μg/kg], GL-S [5, 15, 45 μg/kg], GL-G [15 μg/kg]), scopolamine butylbromide (0.4 mg/kg), or saline was administered intravenously 20 min after the termination of spontaneous phase III contractions, and blood samples were taken at 5- to 10-min intervals. Barium was administered into the stomach 10 min after the infusion of each drug. The arrival of a barium meal in the stomach immediately stimulated gastrointestinal contractions, and the barium meal was expelled into the duodenum and jejunum from the stomach. Intravenous injection of 15 μg GL-S first stimulated duodenal contractions that propagated to the jejunum, followed by strong inhibition of the barium-induced gastrointestinal contractions. This inhibitory effect of glucagon and the activity of the glucagon-induced duodenal contractions were dose-related. The inhibitory effects of GL-G and GL-S were stronger than that of GL-P. Blood glucose and plasma insulin concentrations were raised after intravenous injection of each glucagon preparation, but there was no difference among the three preparations and no dose relationship. The inhibitory effects of glucagon depend on the material purity and dose, and the inhibitory mechanism was independent of any effect on carbohydrate metabolism. Glucagon administration caused phase III-like contractions in the duodenum and jejunum, which may be responsible for the side effects of glucagon. (Received Jan. 8, 1998; accepted June 26, 1998)     

Sinomenine and magnoflorine,major constituents of Sinomeni Caulis et Rhizoma,show potent protective effects against membrane damage induced by lysophosphatidylcholine in rat erythrocytes

The effects of the water extract of Sinomeni Caulis et Rhizoma (SCR-WE) and its major constituents, sinomenine (SIN) and magnoflorine (MAG), on moderate hemolysis induced by lysophosphatidylcholine (LPC) were investigated in rat erythrocytes and compared with the anti-hemolytic effects of lidocaine (LID) and propranolol (PRO) as reference drugs. LPC caused hemolysis at concentrations above the critical micelle concentration (CMC), and the concentration of LPC producing moderate hemolysis (60 %) was approximately 10 μM. SCR-WE at 1 ng/mL–100 μg/mL significantly inhibited the hemolysis induced by LPC. SIN and MAG attenuated LPC-induced hemolysis in a concentration-dependent manner from very low to high concentrations (1 nM–100 μM and 10 nM–100 μM, respectively). In contrast, the inhibiting effects of LID and PRO on LPC-induced hemolysis were observed at higher concentrations (1–100 μM) but not at lower concentrations (1–100 nM). Neither SIN nor MAG affected micelle formation of LPC, nor, at concentrations of 1 nM–1 μM, did they attenuate the hemolysis induced by osmotic imbalance (hypotonic hemolysis). Similarly, SCR-WE also did not modify micelle formation or hypotonic hemolysis, except at the highest concentration. These results suggest that SIN and MAG potently protect the erythrocyte membrane from LPC-induced damage and contribute to the beneficial action of SCR-WE. The protective effects of SIN and MAG are mediated by some mechanism other than prevention of micelle formation or protection of the erythrocyte membrane against osmotic imbalance.

     

A case of septicemia type Vibrio vulnificus infection with necrotizing fasciitis rescued by lower extremity amputation]

We report a case of septicemia type Vibrio vulnificus infection. The patient was a 74-year-old man who had liver cirrhosis and hepatocelluler carcinoma. He felt a pain in the right femoral lesion after eating raw shellfish (Japanese "Umitake") two days ago. He was admitted to our emergency center due to his shock status and thrombocytopenia two days after the onset. We diagnosed necrotizing fasciitis due to Vibrio vulnificus infection, his life was saved by emergency amputation of the right lower extremity. The culture of the blood and vesicle fluid showed Vibrio vulnificus. There are some reports that the debridement was effective to necrotizing fasciitis due to Vibrio vulnificus infection, but these reports are all about single upper extremity lesion. As far as we know, this is the second report of lower extremity necrotiaong fasciitis due to septicemia type Vibrio vulnificus infection rescued by extremity amputation in Japan. The mortality of septicemia type Vibrio vulnificus infection with necrotizing fasciitis is very high, this is quite a valuable report in making a decision for therapy of septicemia type Vibrio vulnificus infection.     

Celecoxib inhibits production of MMP and NO via down-regulation of NF-κB and JNK in a PGE2 independent manner in human articular chondrocytes

The purpose of this study was to examine the effects of celecoxib on matrix metalloproteinases (MMP-1 and MMP-3), nitric oxide (NO), and the phosphorylation of nuclear factor-κB (NF-κB) and three mitogen-activated protein kinases (MAPKs), (p38, JNK and ERK) in human articular chondrocytes from normal, osteoarthritis, and rheumatoid arthritis cartilages. Celecoxib at 100 nM reduced the IL-1β-induced productions of MMP-1, MMP-3, iNOS, and NO, whereas indomethacin at 100 nM showed no effect. The additional stimulation of prostaglandin E2 (PGE2) failed to restore those productions, while the production of PGE2 were reduced by 1 and 10 μM but not 100 nM of celecoxib. The inhibitors of NF-κB, JNK and p38, but not ERK, decreased IL-1β-enhanced MMP-1, MMP-3 and NO production, respectively, and 100 nM celecoxib down-regulated the phosphorylation of NF-κB and JNK but has no effect on either p38 or ERK. Celecoxib has inhibitory effects on MMP-1, MMP-3 and NO productions, suggesting the protective roles directly on articular chondrocytes. Despite the COX-2 selectivity, celecoxib affects those productions via not PGE2 but NF-κB and JNK MAPK.     

Age-related changes in the electrophysiologic properties of the atrium in patients with no history of atrial fibrillation

Although atrial fibrillation is a common arrhythmia, especially in the elderly, little is known about age-related changes in the electrophysiologic properties of the atrium. The aim of this study was to analyze the effect of aging on atrial vulnerability to atrial fibrillation. An electrophysiologic study was performed in 45 patients with no history of atrial fibrillation, Wolff-Parkinson-White syndrome, structural heart disease, or conditions with potential effects on cardiac hemodynamic or electrophysiologic function (15 females; mean age, 52 +/- 18 years; range, 14 to 84 years). The following atrial excitability parameters were assessed: spontaneous or paced (A1) and extrastimulated (A2) atrial electrogram widths, percent maximum atrial fragmentation (A2/A1 x 100), effective refractory period, wavelength index (ERP/A2), and inducibility of atrial fibrillation. Atrial fibrillation was induced in 9 patients. Percent maximum atrial fragmentation was greater (176 +/- 36 vs 137 +/- 26%, P < 0.001) and wavelength index was shorter (2.4 +/- 0.4 vs 3.2 +/- 0.9, P < 0.01) in the patients with than without inducible atrial fibrillation. However, age was similar in patients with and without inducible atrial fibrillation (47 +/- 11 vs 53 +/- 19 years, P = 0.36). Percent maximum atrial fragmentation and effective refractory period directly correlated with age (r = 0.32, P < 0.05 and r = 0.45, P < 0.001, respectively). On the other hand, wavelength index (3.1 +/- 0.9) did not correlate with age (r = -0.05, P = 0.77). This study suggests that the mechanism triggering atrial fibrillation may be very well different between older and younger patients with atrial fibrillation, because younger patients have no marked substrate for atrial fibrillation.     

Cytokinin/auxin balance in crown gall tumors is regulated by specific loci in the T-DNA

Insertion of the transposon Tn5 into the T-region of the octopine Ti plasmid of Agrobacterium tumefaciens gives rise to crown gall tumors having altered morphology. Three loci within the T-DNA that control tumor morphology have been detected [Garfinkel, D. J., Simpson, R. B., Ream, L. W., White, F. F., Gordon, M. P. & Nester, E. W. (1981) Cell 27, 143-153]. They influence tumor size (tml), production of roots (tmr), or production of shoots (tms). Cytokinin and auxin levels in such mutant tumors were examined by HPLC/radioimmunoassay and HPLC/fluorescence assay, respectively. Free indoleacetic acid levels (in pmol/g) were: uninfected tobacco stem tissues, 128; wild-type A348 tumors, 295; tml mutant tumors, 307; tmr mutant tumors, 129; and tms mutant tumors, 70. Average trans-ribosylzeatin levels were correspondingly: 0.97, 48, 40, 0.54, and 1,400 pmol/g. trans-Ribosylzeatin/indoleacetic acid ratios were as high as 24 in shoot-producing tumors and as low as 0.003 in root-producing tumors. The evidence strongly suggests that tumor phytohormone levels are determined by genes in the T-DNA.     

Computer-Aided Diagnosis Scheme for Distinguishing Between Benign and Malignant Masses on Breast DCE-MRI Images Using Deep Convolutional Neural Network with Bayesian Optimization

Although magnetic resonance imaging (MRI) has a higher sensitivity of early breast cancer than mammography, the specificity is lower. The purpose of this study was to develop a computer-aided diagnosis (CAD) scheme for distinguishing between benign and malignant breast masses on dynamic contrast material-enhanced MRI (DCE-MRI) by using a deep convolutional neural network (DCNN) with Bayesian optimization. Our database consisted of 56 DCE-MRI examinations for 56 patients, each of which contained five sequential phase images. It included 26 benign and 30 malignant masses. In this study, we first determined a baseline DCNN model from well-known DCNN models in terms of classification performance. The optimum architecture of the DCNN model was determined by changing the hyperparameters of the baseline DCNN model such as the number of layers, the filter size, and the number of filters using Bayesian optimization. As the input of the proposed DCNN model, rectangular regions of interest which include an entire mass were selected from each of DCE-MRI images by an experienced radiologist. Three-fold cross validation method was used for training and testing of the proposed DCNN model. The classification accuracy, the sensitivity, the specificity, the positive predictive value, and the negative predictive value were 92.9% (52/56), 93.3% (28/30), 92.3% (24/26), 93.3% (28/30), and 92.3% (24/26), respectively. These results were substantially greater than those with the conventional method based on handcrafted features and a classifier. The proposed DCNN model achieved high classification performance and would be useful in differential diagnoses of masses in breast DCE-MRI images as a diagnostic aid.