Advance in animal experiments with the undulation pump total artificial heart: 50 and 54 day survival periods with 1/R control

The undulation pump total artificial heart (UPTAH) is a unique, implantable, total artificial heart (TAH) that uses undulation pumps. To achieve long-term survival in animals with physiologic hemodynamic conditions, a control method based on conductance and arterial pressure was applied to UPTAH. With this control method, called 1/R control, survival periods of 50 days (No. 0016, 49.6 kg) and 54 days (No. 0030, 42.5 kg) were obtained in adult female goats. In No. 0016, 1/R control was applied to the left pump, whereas in No. 0030, it was applied to the right pump. Another pump was used for left-right balance control. The control stability was better in No. 0030 than in No. 0016. The sucking effect of the left atrium was remarkable in No. 0016, possibly because of a time delay when left-right balance control was performed with the right pump. In No. 0016, the cause of death was probably a thrombus flown from a panus in the left atrium. It is possible that the left atrial suction effect influenced the thrombus and panus formation in the left atrium. In No. 0030, the cause of death was a small rupture of the membrane in the right pump. The rupture may have been caused by excessive negative pressure inside the pump. This pressure resulted from suction of the right atrium because of an unexpected control excursion, which was probably caused by a software bug. It will be necessary to redesign the undulation pump and improve the software to achieve longer survival periods for animals with physiologic hemodynamic conditions.     

Sphincter of Oddi contractile function after balloon dilation: detailed manometric evaluation in conscious dogs

BACKGROUND: Endoscopic balloon dilation is under investigation as a treatment modality for bile duct stones. It may have an advantage of preserving the sphincter of Oddi function, but little is known about sphincter of Oddi cyclic motility after dilation. METHODS: Four dogs with a duodenal cannula underwent sphincter of Oddi dilation and repeated manometry to assess sphincter of Oddi cyclic motility until 3 months after dilation. Histologic changes in the sphincter of Oddi were examined in another group of four dogs. RESULTS: Motility index (sum of amplitude of sphincter of Oddi phasic waves counted per minute) and basal pressure decreased on day 3. Sphincter of Oddi amplitude during phase III of the duodenal migrating motor complex tended to be increased on day 3 and decreased to the minimum on day 21. Thereafter, it gradually recovered to baseline. By histology, severe acute inflammation was present in the sphincter of Oddi muscle layer on day 3. However, basal pressure remained significantly low even 3 months after dilation. CONCLUSIONS: Sphincter of Oddi amplitude is incompletely reduced on day 3 after balloon dilation. Sphincter of Oddi basal pressure and motility index in the early phase of sphincter of Oddi cyclic motility remain low for at least 3 months after dilation. Further long-term follow-up is necessary to determine whether sphincter of Oddi function is actually preserved.     

Severe localized stenosis and marked dilatation of the main pancreatic duct are indicators of pancreatic cancer instead of chronic pancreatitis on endoscopic retrograde balloon pancreatography

BACKGROUND: Differentiation between benign and malignant localized stenoses of the main pancreatic duct is difficult by pancreatography. METHODS: A total of 48 patients with such localized stenosis who underwent endoscopic retrograde balloon pancreatography with abdominal compression were retrospectively studied. The following were examined: (1) diameter of the stenotic, prestenotic, and poststenotic ductal segments; (2) ratios of prestenotic/poststenotic, stenotic/prestenotic, and stenotic/poststenotic ductal segments; (3) length of stenosis and steepness of transition to the stenosis (proximal angle, distal angle); and (4) main duct and branch findings for peristenotic segments. RESULTS: The stenosis was diagnosed as caused by chronic pancreatitis in 27 patients and pancreatic cancer in 21 by histopathology, cytology, or clinical follow-up. The prestenotic/poststenotic ductal segments ratio and proximal angle were greater in pancreatic cancer compared with chronic pancreatitis. Severe stenosis (stenotic ductal segments less than 20% of prestenotic or poststenotic ductal segments); moderate (prestenotic ductal segments 2.5 to 3.5 times larger than poststenotic ductal segments), and severe (prestenotic ductal segments more than 3.5 times larger than poststenotic ductal segments) dilatation of the proximal duct were more frequent in pancreatic cancer than in chronic pancreatitis. Multivariate regression analyses showed that severe stenosis and dilatation were independently significant parameters that indicated a diagnosis of pancreatic cancer. Various combinations of severe stenosis, proximal dilatation, and double duct sign gave high predictive values. CONCLUSIONS: Severe stenosis, marked proximal dilatation, double duct sign, and combinations of these findings are useful indicators of malignant localized stenosis of the pancreatic duct.     

Establishment of a new human pancreatic cancer cell line, NOR-P1, with high angiogenic activity and metastatic potential

We present here a new cell line, NOR-P1, established from a metastatic subcutaneous tumor of a patient with pancreatic cancer. The cells show rapid growth in culture with a doubling time of 16 h and high migration activity. Genetic and molecular analyses revealed high telomerase activity and a mutation in the K-ras oncogene. Of particular interest, the cells express markedly elevated mRNA levels of angiogenic factors, vascular endothelial growth factor and platelet-derived growth factor, as well as other tumor growth-related factors. Subcutaneous transplantation of the NOR-P1 cells into nude mice formed solid, hemorrhagic tumors which were histologically diagnosed as adenocarcinoma with dense blood vessels and severe extravasation of blood. Furthermore, when NOR-P1 cell suspension was injected directly into the pancreas of nude mice, the cells grew rapidly to form intra-pancreatic tumors associated with liver metastases and peritoneal dissemination that resulted in cachexia and subsequent death. These properties suggest that NOR-P1 is an aggressive pancreatic cancer cell line with a high metastatic potential and may serve as a useful experimental model for studying tumor angiogenesis and metastasis of pancreatic cancer.     

Involvement of 90K/Mac-2 binding protein in cancer metastases by increased cellular adhesiveness in lung cancer

90K/Mac-2 Binding Protein (M2BP) plays a role in regulation of immune responses and cell adhesive ability in patients with cancer and infectious diseases. We previously reported that M2BP was highly expressed in lung cancer and that immune responses to M2BP were increased in many patients with lung cancer. To determine the involvement of M2BP in metastatic processes of cancer progression, we examined the ability of M2BP DNA-transduced lung carcinoma cell lines to adhere to extracellular matrices. Although expressions of cell-surface integrins were not modulated in the M2BP transfectants, they showed increased adhesiveness to fibronectin and collagen IV. We next analyzed the serum levels of M2BP in patients with lung cancer and normal donors and the relationships between M2BP expression and clinicopathological factors in the patients. The M2BP level was markedly elevated in the patients and was strongly correlated with nodal involvement and clinical staging. To determine whether expression of M2BP by cancer cells is modulated in the environment of tumor-bearing hosts, M2BP expression in M2BP-positive QG56 cells following exposure of the cells to pro-inflammatory cytokines was examined. The M2BP expression in QG56 cells was up-regulated by many of the cytokines that activate host protective immunity. The findings in this study suggest that M2BP plays a role in cancer metastasis by increased adhesiveness of cancer cells and that M2BP is increasingly produced even in a state of exposure to the host immune system. This molecule may be useful as a predictive factor of disease progression in lung cancer.     

Heart preservation using continuous ex vivo perfusion improves viability and functional recovery.

BACKGROUND: Cold static storage (CS) is a proven preservation method for heart transplantion, yet early postoperative graft dysfunction remains prevalent, so continuous perfusion (CP) during ex vivo transport may improve viability and function of heart grafts. METHODS AND RESULTS: Canine hearts underwent CP (n=9) or CS (n=9) for 6 h while intramyocardial pH was continuously monitored. Biopsies were assayed for ATP, caspase-3, malondialdehyde (MDA), and endothelin-1 (ET-1) levels at baseline, after preservation (t1), and after 1 h of blood reperfusion on a Langendorff model (t2). Functional recovery was determined at t2 by +dP/dt, -dP/dt, developed pressure, peak pressure and end-diastolic pressure. CP resulted in higher tissue pH and ATP stores and reduced caspase-3, MDA and ET-1 levels compared with CS at both t1 and t2. Post reperfusion recovery was significantly greater in CP vs CS for all myocardial functional parameters except end-diastolic pressure. Weight gain was significantly increased in CP vs CS at t1, but not at t2. CONCLUSIONS: Low-grade tissue acidosis and energy depletion occur during CS and are associated with oxidative injury and apoptosis during reperfusion. CP attenuates these biochemical and pathologic manifestations of tissue injury, together with improved myocardial recovery, despite mild, transient edema.     

Pain associated with phase III of the duodenal migrating motor complex in patients with postcholecystectomy biliary dyskinesia

BACKGROUND: Correlation between various gastrointestinal events and particular aspects of the migrating motor complex has been reported. This study correlates postcholecystectomy pain to variations in biliary pressure associated with the duodenal motor cycle. METHODS: In 18 patients with postcholecystectomy pain and 10 control subjects, biliary and duodenal pressures were recorded simultaneously with microtransducers. After recording a spontaneous cycle, morphine was administered to induce a premature phase III and spasm of the sphincter of Oddi, and then cerulein was administered to stop the spasm. RESULTS: Transient but significant elevations of biliary pressure occurred at duodenal phase III in both groups, but a greater percentage of the patients developed pain during phase III (89% vs. 20%, p<0.01). Morphine produced premature phase III and biliary pressure elevation, which were accompanied by pain more frequently in the patients than in the control subjects (78% vs. 30%, p<0.05). Biliary pressure dropped after the cerulein injection, relieving the pain in 13 of 14 patients and in 2 of 3 control subjects who had morphine-induced pain. The phase III-related pain was relieved by endoscopic sphincterotomy in 14 of 15 patients. CONCLUSIONS: The cyclic elevation of biliary pressure in coordination with phase III of the duodenal motor cycle may contribute to the development of pain in patients with postcholecystectomy biliary dyskinesia.     

Effects of paraquat on mitochondrial electron transport system and catecholamine contents in rat brain

 The effects of paraquat on rat brain were studied. Activities of complex I (NADH: ubiquinone oxidoreductase) in mitochondrial electron transport system, lipid peroxidation and the amount of catecholamines in rat brain were measured after acute paraquat exposure. Complex I activities were significantly lower and lipid peroxides were higher in the brains of a paraquat-treated group than in those of a control group. Lipid peroxide in rat serum, however, did not increase after paraquat exposure. A study of the time dependency of paraquat effects disclosed that mitochondrial complex I activities in rat brain as well as those in rat lung and liver gradually decreased prior to the appearance of respiratory dysfunction. As compared to controls, the dopamine in rat striatum was significantly lower in the paraquat-treated group. These results suggest that paraquat after crossing the blood-brain barrier might be reduced to the radical in rat brain, which may damage the brain tissue, especially dopaminergic neurons in striatum. We therefore propose that cerebral damage should be taken into consideration on paraquat exposure. Patients may therefore need to be followed up after exposure to high doses of paraquat. Received: 19 June 1995/Accepted: 18 January 1996     

The progression potential of peritoneal dissemination nodules from gastrointestinal tumors

It is necessary to examine the characteristics of the dissemination nodules to establish a therapeutic strategy for peritoneal dissemination from digestive malignancy. Ki-67 expression as a proliferation marker in peritoneal dissemination nodules was investigated. The subjects were 15 patients with gastrointestinal cancers who underwent resection of the primary tumor and disseminated nodules. The expression of Ki-67 in both primary tumor and peritoneal dissemination nodule from each patient was evaluated by immunohistochemistry. Ki-67 labeling index in the original tumor was higher than that in the disseminated nodule in 13 of 15 patients (P < 0.0001). The mean value of Ki-67 labeling index was 42.2% in the 15 original tumors and 18.7% in the 15 disseminated nodules. Proliferative activity in the disseminated nodules was lower than that in the primary tumors. Further examination about characteristics of cancer dissemination is needed to treat patients with peritoneal metastasis.