A 10 Minute Self-Care Program May Reduce Breast Cancer-Related Lymphedema: A Six-Month Prospective Longitudinal Comparative Study.

Patients with breast cancer-related lymphedema (BCRL) need a life-long self-care program that they can adhere to enable them to manage their lymphedema. The objective of this study was to assess the effectiveness of a holistic BCRL self-care program that patients could easily adhere to and comply with. A prospective, longitudinal, comparative study between affected arms and unaffected arms in unilateral breast cancer patients was implemented over a six-month period. Both the lymphedematous and unaffected arms of 23 patients with unilateral BCRL were followed and measured. The daily 10-minute holistic BCRL self-care program consisted of modified Japanese rajio taiso (Japanese radio calisthenics), a gentle arm exercise combined with deep breathing, skin moisturizing care using a traditional lymphatic drainage technique, and basic self-care education. Arm and edema volume, relative volume change, resistance of the skin to compression (fibrosis), lymphedema-related symptoms, skin condition, and self-care were assessed. At the end of six-months the volume of all limb segments and resistance of the tissues to compression at all measurement points of the affected arm were significantly reduced. On the unaffected side, only the volume of the forearm and the whole arm was significantly reduced and fibrosis significantly reduced only in the forearm. There was no significant difference in edema volume and relative volume change. Lymphedema-related symptoms significantly improved. Perceived adherence, effectiveness, burden, score and average time for self-care significantly increased. Our results demonstrate that this 10-minute self-care program may improve BCRL and its self-care.

Membrane fluidity correlates with liver cancer cell proliferation and infiltration potential.

We developed a method to measure membrane fluidity of living cancer cells in two- and three-dimensional cultures, and found that there was a close relationship between the membrane fluidity of cancer cells and their proliferative and infiltrative ability. Membrane fluidity is thus a promising indicator of the probability of cancer recurrence.

Perioperative quantitative analysis of cytokeratin 20 mRNA in peripheral venous blood of patients with colorectal adenocarcinoma.

Hematogenous dissemination is a significant short-coming of colorectal carcinoma treatment. To screen patients with high risk for such blood-borne metastasis, we previously developed a highly sensitive system for the detection of cytokeratin 20 (CK-20) mRNA in blood. For a more practical application, we improved this system by making it quantitative and capable of analyzing peripheral venous blood for the detection of perioperative changes in CK-20 mRNA. CK-20 mRNA was not always detected in the preoperative blood, even in patients in an advanced stage, but it was identified without fail in intra- and post-operative blood. In addition, more copies of CK-20 mRNA were observed in the intra-operative blood than in pre- and post-operative blood. This study suggests that analysis of perioperative changes may provide important information for the precise evaluation of hematogenous dissemination and of the effect of surgical maneuvers on recurrence.

Effect of the oral administration of sepimostat mesilate on cerulein induced acute pancreatitis in rats.

The effect of a potent protease inhibitor, sepimostat mesilate (CAS 103926-82-5, FUT-187), on acute interstitial edematous pancreatitis induced by a supramaximal dose of cerulein, a cholecystokinin (CCK) analogue, was evaluated. The serum amylase activity increased 18-fold over normal control after the infusion of cerulein at 5 micrograms/kg/h for 6 h. The serum lipase activity showed a 235-fold increase. An elevated pancreatic water content, pancreatic interstitial edema, inflammatory infiltration and vacuolization of the acinar cells were found. Redistribution of cathepsin B shifted from the lysosomal pellet fraction to the zymogen granule pellet fraction was noted in the early stages. All these parameters of pancreatitis mentioned above were inhibited by FUT-187 pretreatment at doses of 30 to 300 mg/kg. These observations suggest that FUT-187 inhibits the redistribution of cathepsin B shift from the lysosomal fraction to the zymogen fraction in cerulein-induced acute pancreatitis and improves the parameters of acute pancreatitis.

Gastric mucosal EGF and PDGF receptor expression with ulcer healing by ebrotidine.

OBJECTIVES: Epidermal growth factor (EGF) and platelet-derived growth factor (PDGF) play important roles in the process of mucosal repair and restitution, and their biological effects are mediated by receptors located on the target cell surfaces. The purpose of this study was to assess the effect of the antiulcer agent, ebrotidine, on the expression of EGF and PDGF receptors with chronic ulcer healing. METHODS: Chronic gastric ulcers were developed in the rat by acetic acid technique. The animal were divided into two groups and were treated twice daily for 14 consecutive days, either with ebrotidine at 100 mg/kg, or placebo. At different stages of treatment, the animals were sacrificed and used for the isolation and quantification of gastric mucosal EGF and PDGF receptors. RESULTS: The binding assays revealed that ulcer healing was accompanied by an increase in mucosal expression of both types of receptors. A 1.7-1.8-fold increase in PDGF and EGF receptors occurred by the 4th day after the development of ulcer and reached a maximum of 3-fold increase by the 14th day, when the ulcer was essentially healed. Treatment with ebrotidine caused accelerated ulcer healing (7 days) which was accompanied by a significant enhancement in receptor expression. Compared to the controls, a 1.5-fold increase in EGF and 1.7-fold increase in PDGF receptor expression occurred by the 7th day of ebrotidine treatment, and a 1.4- to 1.5-fold increase was still observed at the 14th day of treatment. CONCLUSIONS: The results suggest that ebrotidine is capable of enhancement of gastric mucosal proliferative activities associated with ulcer healing through the stimulation of EGF and PDGF receptor expression.

Gastric mucosal laminin receptor expression with ulcer healing by ebrotidine.

1. The effect of antiulcer agent, ebrotidine, on the expression of gastric mucosal laminin receptor during ulcer healing was investigated. 2. Rats with acetic acid-induced chronic gastric ulcers were treated twice daily for 14 consecutive days either with ebrotidine at 100 mg/kg or placebo, and then at different stages of treatment used for the isolation and quantitation of gastric mucosal laminin receptor. 3. The binding assays revealed that the ulcer healing was accompanied by an increase in mucosal expression of laminin receptor. A 2.7-fold increase in the receptor expression occurred by 4th day following the development of ulcer and reached a maximum of 8.6-fold increase by the 14th day when the ulcer was essentially healed. 4. Treatment with ebrotidine caused accelerated ulcer healing (7 days), which was accompanied by a remarkable enhancement in the laminin receptor expression. A 2.5-fold increase in the receptor expression over that of controls occurred by the 4th day of ebrotidine treatment, and a 1.7-fold increase was still observed at the 14th day of treatment. 5. The results suggest that ebrotidine, by evoking enhanced mucosal cell laminin receptor expression, promotes reepithelization and, hence, hastens the ulcer healing.

Association of salivary bacterial aggregating activity with sulfomucin.

The requirements of human salivary mucins for aggregating potential towards the common cariogenic oral bacteria, S. mutans and S. sanguis, were investigated. Agglutination inhibition assays demonstrated that the aggregating capacity towards bacteria resides in the acidic mucin fraction. The inhibitory activity of the acidic mucin decreased only 2-4-fold following removal of sialic acid, whereas the desulfation caused a complete loss of the inhibitory potential against both bacteria. Furthermore, the aggregating capacity of mucin-derived sulfated oligosaccharide was found to be 16-fold higher than that of the sialic acid containing oligosaccharide. The results point towards the importance of salivary sulfomucins as a predominant factor in the defense of oral cavity against cariogenic bacteria.

Regulation of gastric mucosal calcium channel activity by an antiulcer agent, ebrotidine.

Ebrotidine is a new H2-receptor antagonist also known for its gastroprotective effect against ethanol-induced mucosal injury. In this study, we investigated the effect of ebrotidine on the activity of the gastric mucosal calcium channels. The channel complex was isolated from the solubilized gastric epithelial cell membranes by affinity chromatography on wheat germ agglutinin. The complex following labeling with [3H] PN200-110 was reconstituted into phosphatidylcholine vesicles which exhibited active 45Ca2+ uptake into intravesicular space and responded in a concentration-dependent manner to calcium channel activator, BAY K8644, as well as to calcium channel antagonist, PN200-100. The 45Ca2+ uptake was inhibited by ebrotidine which caused maximum inhibitory effect of 54.9% at 50 micrograms/ml. The gastric mucosal calcium channels on epidermal growth factor binding (EGF) in the presence of ATP responded by an increase in tyrosine phosphorylation of 55 and 170 kDa proteins, and the vesicles containing the phosphorylated channels displayed a 48% greater 45Ca2+ uptake. This phosphorylation process was inhibited by ebrotidine which also interfered with the binding of EGF to calcium channel protein. The results point towards the importance of EGF in the maintenance of gastric mucosal calcium homeostasis, and suggest that ebrotidine has the ability to protect the cellular integrity from calcium imbalance by modulating the EGF-stimulated gastic mucosal calcium channel phosphorylation.

Sulglycotide effect on the proteolytic and lipolytic activities of Helicobacter pylori toward gastric mucus.

OBJECTIVES: Infection with Helicobacter pylori is now recognized as a major factor in the etiology of gastric disease, and among the detrimental effects this bacterium exerts on the mucosal integrity is the elaboration of extracellular protease and lipase enzymes capable of mucus protein and lipids degradation. We present here evidence that the activities of these enzymes are inhibited by an gastroprotective agent, sulglycotide. METHODS: The grown colonies of bacterium were washed with saline, filtered through sterilization filter, and the filtrate used as the enzyme source. RESULTS: In the absence of sulglycotide, the H. pylori protease caused extensive degradation of human gastric mucus, while free fatty acids, glycerol monooleate and lysophosphatidylcholine were produced by the action of H. pylori lipase and phospholipase A enzymes. Introduction of sulglycotide to the incubation systems led to the reduction in the rate of mucus protein and lipid degradation. The rate of proteolysis inhibition was proportional to sulglycotide concentration up to 45 micrograms/ml, at which point a 43% reduction in mucus degradation was attained, whereas the maximum inhibition of lipase (39%) and phospholipase A (98%) activities occurred at a sulglycotide concentration of 100 micrograms/ml. CONCLUSIONS: This study indicates that sulglycotide is capable of counteracting the mucolytic activity of H. pylori, and thus may be of value in the therapy of H. pylori-associated gastric diseases.

Platelet-activating factor involvement in the aggravation of acute pancreatitis in rabbits.

Platelet activating factor (PAF) was administered to anesthetized rabbits with cerulein-induced acute pancreatitis to investigate the role of PAF in the development of acute pancreatitis. In acute edematous pancreatitis, induced with cerulein 20 micrograms/kg/h i.v. for 5 h, blood flow in the gastroduodenal and superior mesenteric arteries (GDAF and SMAF) had decreased significantly by 30 min and the serum amylase and lipase levels were significantly increased in the early phase. In the cerulein+PAF group, in which PAF was injected 100 ng/kg/min i.v. for 20 min simultaneously with cerulein, GDAF and SMAF declined significantly to 52 +/- 4 and 47 +/- 3% (p < 0.05), serum amylase and lipase levels rose significantly to 1,110 +/- 150 and 1,370 +/- 190% (p < 0.01) at 300 min, much higher than in the cerulein group. Furthermore, scattered hemorrhages and more marked inflammatory cell infiltration were observed histologically. These findings suggest that PAF has an additive role in the aggravation of acute pancreatitis.

Helicobacter pylori lipopolysaccharide inhibition of gastric mucosal laminin receptor: effect of sulglycotide.

1. The effect of cell-wall lipopolysaccharide from Helicobacter pylori, a bacterium implicated in the etiology of gastric disease, on the gastric mucosal laminin-receptor was investigated. 2. The receptor, isolated from gastric epithelial cell membrane by affinity chromatography on laminin-coupled Sepharose, was radioiodinated and incorporated into liposomes which exhibited specific affinity towards laminin-coated surface. 3. The binding of liposomal receptor to laminin-coated surface was inhibited by H. pylori lipopolysaccharide, which at 50 micrograms/ml caused a nearly complete (97%) inhibition in binding. 4. The inhibitory effect of the lipopolysaccharide was prevented by a cytoprotective agent, sulglycotide, that evoked a 92% restoration in binding at 40 micrograms/ml. 5. The results demonstrate that through its lipopolysaccharide H. pylori is capable of disrupting the gastric mucosal integrity and that this detrimental effect could be successfully countered by sulglycotide.

Role of pancreatic blood flow and vasoactive substances in the development of canine acute pancreatitis.

To study the role of pancreatic blood flow and vasoactive substances in the development of acute pancreatitis, we measured portal vein blood levels of bradykinin, prostaglandin E2 (PGE2), histamine, serotonin, and pancreatic enzymes, and with an electromagnetic blood flowmeter we recorded gastroduodenal arterial flow (GDAF), superior mesenteric arterial flow (SMAF), and mean arterial blood pressure for 6 hr in dogs with acute hemorrhagic necrotizing pancreatitis induced by the retrograde injection of autologous bile (0.5 ml/kg) into the pancreatic duct. GDAF and SMAF decreased immediately in the early phase of acute pancreatitis (-17.8 +/- 6.1%** at 10 min and -15.8 +/- 7.1%* at 20 min; *P < 0.05, **P < 0.01); portal bradykinin concentration increased quickly (3.2 +/- 1.2 pM at 0 time, 16.2 +/- 5.2 pM* at 5 min, 30.4 +/- 4.8** pM** at 10 min, and 39.6 +/- 15.1 pM* at 20 min). Portal PGE2 concentration increased gradually after the induction of acute pancreatitis, and differences from the control group were significant at 20, 30, and 180 min (1426 +/- 175 pM at 0 time, 1956 +/- 273 pM* at 20 min, 2148 +/- 265 pM** at 30 min, and 3369 +/- 686 pM* at 180 min). Portal histamine and serotonin concentrations increased somewhat, but not significantly. These findings suggest that the injection of bile into the pancreatic duct causes the pancreas to quickly release a large amount of bradykinin into the portal vein, which immediately reduces the pancreatic blood flow in the early phase, thus accelerating the progress of acute pancreatitis.

Effect of prostaglandin E2 on cellular, lysosomal and mitochondrial fragility in caerulein-induced pancreatitis in rats.

The effects of prostaglandin E2 on the fragility of cellular and subcellular organelles in caerulein-induced acute pancreatitis were investigated in rats. PGE2 at doses of 50 and 100 micrograms/kg/hr infused for 2 hours before and during caerulein (5 micrograms/kg/hr for 3.5 hours) infusion significantly prevented the increased discharge of both amylase and lactate dehydrogenase from dispersed acini, and the leakage of cathepsin B from lysosomes and of malate dehydrogenase from mitochondria in the subcellular fraction in vitro. These results suggest that PGE2 has a cytoprotective effect against caerulein-induced pancreatitis by stabilizing cell and lysosomal and mitochondrial membranes.

Enhancement in gastric mucosal laminin receptor expression with ulcer healing.

The expression of gastric mucosal laminin receptor with chronic ulcer healing was investigated. The receptor protein was isolated from gastric epithelial cell membrane of rats at various stages of ulcer healing and following radioiodination incorporated into vesicles which exhibited specific affinity towards laminin-coated surface. The binding assays revealed that the ulcer healing was accompanied by an increase in laminin receptor expression. A significant increase (2.5-fold) in the receptor expression occurred by the third day following the development of ulcer, reached a maximum of 8.6-fold increase by the 14th day when the ulcer was virtually healed, and its high level remained for at least 20 days. The results demonstrate the importance of laminin receptor as an indice of gastric mucosal repair in ulcer healing.

Regulation of buccal mucosal calcium channel activity by salivary mucins.

1. The effect salivary mucins on the activity of calcium channel isolated from buccal mucosal cell membranes was investigated. The uptake of 45Ca2+ while only moderately (15%) affected by the intact low and high molecular weight mucin forms, was significantly inhibited, by the acidic low and high molecular weight salivary mucins which evoked 64 and 60% inhibition, respectively. 2. The inhibitory effect of salivary mucins was associated with the sialic acid and sulfate ester groups of the carbohydrate chains, as the removal of either group caused partial loss in the glycoproteins inhibition, and the complete loss in the inhibitory effect occurred following desialylation and desulfation. 3. The channel in the presence of epidermal growth factor (EGF) and ATP responded by an increase in tyrosine phosphorylation of 55 and 170 kDa proteins, and the phosphorylated channels showed a 46% increase in 45Ca2+ uptake. The phosphorylation and the calcium uptake were susceptible to inhibition by a specific tyrosine kinase inhibitor, genistein. 4. The binding of EGF to calcium channel receptor protein was inhibited by the low and high molecular weight acidic mucins, causing 41.2 and 36.1% reduction, respectively. This reduction in binding was dependent upon the presence of sulfate ester and sialic acid groups, as evidenced by the loss of the glycoproteins' inhibitory capacity following removal of these groups. 5. The results for the first time demonstrate that salivary mucins actively participate in the modulation of the EGF-controlled buccal mucosal calcium channel activity expression, a process of importance to the preservation of oral tissue integrity.

Effect of ebrotidine on gastric mucosal EGF and PDGF receptor expression.

The effect of ebrotidine, a new H2-blocker with gastroprotective properties, on the expression of gastric mucosal epidermal growth factor (EGF) and platelet-derived growth factor (PDGF) receptors, was investigated. Mucosal cell membranes were isolated from rats receiving twice daily for 5 days a dose of 100mg/kg ebrotidine or 100mg/kg ranitidine or vehicle only. Assays for EGF and PDGF revealed the presence of both types of receptors, activation of which led to enhanced tyrosine kinase activity. The receptor binding values in the control group were 2.4 fmol for EGF and 1.45 fmol/mg protein for PDGF, whereas the values in the ebrotidine group increased for EGF by 65.7% and 38.6% for PDGF, but no such effect was observed with ranitidine. The results suggest that the gastroprotective properties of ebrotidine stem from its ability to stimulate the epithelial proliferative activities through the enhancement of EGF and PDGF receptors expression.

Inhibition of Helicobacter pylori colonization by an antiulcer agent, sulglycotide.

Sulglycotide, a potent antiulcer agent derived from duodenal mucus glycopeptide through sulfation of the carbohydrate moieties, was evaluated with respect to its ability to interfere with H. pylori mucosal attachment. H. pylori cells were incubated with sulglycotide or human gastric mucin and then examined for their inhibitory capacity of H. pylori attachment to erythrocytes. Titration data revealed that the mucin inhibitory activity was confined to its sulfomucin fraction, the titer of which was found to be 16-fold higher than that of intact mucin. The data with sulglycotide showed that the inhibitory titer of this agent against H. pylori attachment was at least 30-fold higher than that of the sulfated gastric mucin fraction. The results point towards the involvement of sulfomucins in the protection of gastric mucosa from H. pylori colonization and demonstrate that sulglycotide, because of structural similarities, is ideally suited to augment the inherent mucosal defenses against this pathogen.

Effect of prostaglandin E on the redistribution of lysosomal enzymes in caerulein-induced pancreatitis.

The redistribution of cathepsin B, a representative lysosomal enzyme, from the lysosomal pellet to the zymogen pellet in subcellular fractions and the colocalization of cathepsin B with digestive enzymes within acinar cells have been found during the early stage of caerulein-induced acute pancreatitis in the rat. This study investigated the protective effects of prostaglandins E1 and E2 on the exocrine pancreas in this experimental pancreatitis. Prostaglandin E2, but not E1, prevented the redistribution of cathepsin B along with the hyperamylasemia, and the increase in amylase and trypsinogen in the acinar cells in almost a dose-dependent manner, particularly at a dose of 100 micrograms/kg.hr of continuous infusion. These results suggest that subcellular organelle fragility is closely related to the pathogenesis of acute pancreatitis, and that prostaglandin E2 has an important cytoprotective effect on biological membranes as a stabilizer of lysosomal membrane.

Bradykinin involvement in the aggravation of acute pancreatitis in rabbits.

This study was designed to investigate the role of bradykinin in the aggravation of acute pancreatitis. After injection of bradykinin 2 micrograms/kg to anesthetized rabbits with cerulein-induced acute pancreatitis, the pancreatic blood flow through gastroduodenal and superior mesenteric arteries (GDAF and SMAF) was determined with electromagnetic blood flow meters, the serum amylase level was measured, and pancreatic tissue was observed histologically. In rabbits treated with a supramaximal dose of cerulein alone (20 micrograms/kg/h), pancreatic blood flow was decreased and the serum amylase level was increased significantly by the early phase, and histological examination showed acute edematous pancreatitis. In rabbits treated with cerulein and bradykinin, GDAF and SMAF were significantly diminished at 300 min (51 +/- 5% and 50 +/- 4%, respectively, p < 0.05), and the serum amylase level rose significantly at 180 and 300 min (730 +/- 130% and 1,190 +/- 200%, respectively, p < 0.01) compared with rabbits treated with cerulein alone, and histological examination revealed pancreatic necrosis and greater inflammatory cell infiltration. These findings suggest that bradykinin has an additive role in the aggravation of acute pancreatitis.

Protective effect of nafamostat mesilate on cellular and lysosomal fragility of acinar cells in rat cerulein pancreatitis.

This in vivo and in vitro study demonstrates the protective effects of a new synthetic protease inhibitor--nafamostat mesilate, FUT-175--on increased cellular and lysosomal fragility within acinar cells during the early stage of cerulein-induced acute pancreatitis in rats. FUT-175 prevented hyperamylasemia, pancreatic edema, congestion owing to amylase, and lactic dehydrogenase (LDH) discharge from acini as well as cathepsin-B leakage from lysosomes dose-dependently in doses of 1-10 mg/kg.h. These results suggest that FUT-175 can protect against pancreatitis at subcellular levels in lysosomes and cellular or organelle membranes. Proteases may well play the important role in the pathogenesis of acute pancreatitis, and such a low molecular protease inhibitor may be useful clinically in the treatment of acute pancreatitis.