The interaction of Fc alpha RI with IgA and its implications for ligand binding by immunoreceptors of the leukocyte receptor cluster.

This study defines the molecular basis of the FcalphaRI (CD89):IgA interaction, which is distinct from that of the other leukocyte Fc receptors and their Ig ligands. A comprehensive analysis using both cell-free (biosensor) and cell-based assays was used to define and characterize the IgA binding region of FcalphaRI. Biosensor analysis of mutant FcalphaRI proteins showed that residues Y35, Y81, and R82 were essential for IgA binding, and R52 also contributed. The role of the essential residues (Y35 and R82) was confirmed by analysis of mutant receptors expressed on the surface of mammalian cells. These receptors failed to bind IgA, but were detected by the mAb MY43, which blocks IgA binding to FcalphaRI, indicating that its epitope does not coincide with these IgA binding residues. A homology model of the ectodomains of FcalphaRI was generated based on the structures of killer Ig-like receptors, which share 30-34% identity with FcalphaRI. Key structural features of killer Ig-like receptors are appropriately reproduced in the model, including the structural conservation of the interdomain linker and hydrophobic core (residues V17, V97, and W183). In this FcalphaRI model the residues forming the IgA binding site identified by mutagenesis form a single face near the N-terminus of the receptor, distinct from other leukocyte Fc receptors where ligand binding is in the second domain. This taken together with major differences in kinetics and affinity for IgA:FcalphaRI interaction that were observed depending on whether FcalphaRI was immobilized or in solution suggest a mode of interaction unique among the leukocyte receptors.

Drug-induced gastropathy in elderly Taiwanese.

BACKGROUND/AIMS: Drug-induced gastropathy was common in developing countries in which drug consumption was heavy. The aim of this study is to evaluate the difference in the distribution of clinical features and endoscopic findings between elderly and non-elderly and to determine the risk factors of drug-induced gastrointestinal mucosal damage in elderly. METHODOLOGY: Four hundred and fifty patients with gastrointestinal mucosal damages were recruited from the outpatient clinic or emergency room. All patients were confirmed by endoscopic examination with Olympus Videoscope QX-200 or GIF-p20. Patient's clinical symptoms, endoscopic findings and risk factors were collected. Data was analyzed by chi 2 test and expressed as Odds ratio. RESULTS: The age distribution of gastropathy was predominant at 60-69 years old, and the case number gradually declined as age increased or decreased, respectively. The clinical presentation of asymptomatic bleeding was significantly higher in the elderly than in the non-elderly, while epigastric pain combined with dyspepsia or bleeding was not different between elderly and non-elderly groups. The endoscopic findings of gastric ulcer and erosions were significantly predominant in the elderly group, while no difference was found for duodenal ulcer between these 2 groups. Non-steroidal anti-inflammatory drugs were the popular drug which lead to gastropathy in both elderly and non-elderly groups. Drugs, especially steroids, history of arthritis or peptic ulcer, and alcohol consumption were found to be the risk factors associated with increased risk of gastropathy in the elderly. Stress was also significantly associated with increased risk of gastropathy in the non-elderly. There was no significant difference in smoking habit and use of other drugs between these 2 groups. CONCLUSIONS: The clinical features of symptoms, endoscopic findings and risk factors of gastropathy varied significantly between the elderly and the non-elderly. Drug-induced gastropathy, especially steroid treatment for arthritis, was a significant risk factor in the elderly. Program for assessment and management of these elderly patients under treatment is important.

Endoscopic variceal ligation in prophylaxis of first variceal bleeding in cirrhotic patients with high-risk esophageal varices.

To determine the efficacy of endoscopic variceal ligation (EVL) in prophylaxis on the rate of first esophageal variceal bleeding, we conducted a prospective, randomized trial in 126 cirrhotic patients with no history of previous upper gastrointestinal bleeding and with esophageal varices endoscopically judged to be at high risk of hemorrhage. The end-points of the study were bleeding and death. Life-table curves showed that prophylactic EVL significantly diminished the rate of variceal hemorrhage (12/62 [19%] vs. 38/64 [60%]; P = .0001) and overall mortality (17/62 [28%] vs. 37/64 [58%]; P = .0011). The 2-year cumulative bleeding rate was 19% (12/ 62) in the EVL group and 60% (38/64) in the control group. The 2-year cumulative mortality rate was 28% (17/62) in the EVL group and 58% (37/64) in the control group. Comparison of Kaplan-Meier estimates of the time to death of both groups showed significantly lower mortality in the ligation group (P = .001). Patients undergoing EVL had few treatment failures and died mainly of hepatic failure. The lower risk in the EVL group was attributed to a rapid reduction of variceal size. Prophylactic EVL was more efficient in preventing first bleeding in patients with good condition (Child A) than in those with decompensated disease (Child B and C). We conclude that prophylactic EVL can decrease the incidence of first variceal bleeding and death over a period of 2 years in cirrhotic patients with high-risk esophageal varices.

Effect of verapamil on renal haemodynamics in a portal hypertensive rat model.

In order to investigate the effects of verapamil on renal haemodynamics in rats with portal hypertension, verapamil was given at either a low (0.2 mg/kg) or high (2 mg/kg) dose to rats after portal vein ligation. An approximate 12% decrease in mean arterial pressure followed administration of low dose verapamil, with a significant decrease in cardiac output and renal blood flow, as well as reduced portal pressure, observed; these signs were all indicative of a rise in renal vascular resistance. In contrast, the marked fall in both mean arterial pressure and cardiac output with high dose verapamil, accompanied by a significant decrease in portal pressure and no change in renal blood flow, suggests a reduction in renal vascular resistance. This study shows that the acute effects of verapamil on renal haemodynamics may vary with the dose used. Also, acute verapamil administration tends to decrease renal blood flow to alter the autoregulation of the kidney; thus, caution should be taken in the clinical use of verapamil in the treatment of cirrhosis with portal hypertension.

Relationship between C14 urea breath test values and solid-phase gastric emptying time in non-ulcer dyspepsia patients.

BACKGROUND: Non-ulcer dyspepsia (NUD) is a poorly understood syndrome often found with endoscopic evidence of gastritis; Helicobacter pylori (Hp) is a common and important cause of gastritis. In the recent literature, gastric hypomotility is thought to be a cause of NUD. Thus, this investigation studied the relationship between Hp and delayed gastric emptying in NUD patients. METHODS: Using a radionuclide-labelled solid meal to calculate gastric emptying time (GET) of 78 NUD patients. The carbon-14 urea breath test (C14 UBT) was used to quantitate Hp infection. RESULTS: The prevalence of Hp infection in patients with NUD reached 59%. There was a strong association of Hp infection with advanced age (p = 0.0091). There was no significant difference between solid-phase GET and C14 UBT values among three different age groups (young, middle, old) of NUD patients. There was no difference among sex, age, body weight and solid-phase GET between Hp-positive and Hp-negative NUD patients. However the solid-phase GET was significantly prolonged in patients with NUD, compared with the controls. CONCLUSIONS: Solid-phase GET is not correlated with the C14 UBT values, and Hp gastric colonization does not account for dyspeptic syndrome in NUD patients.

Relationships between the severity of cirrhosis and haemodynamic values in patients with cirrhosis.

The relationship between the severity of cirrhosis and systemic and hepatic haemodynamic values was evaluated in 193 patients with cirrhosis, most of whom were diagnosed with post-necrotic cirrhosis. It was found that the hepatic venous pressure gradient and cardiac output in Pugh's A patients (13.6 +/- 4.8 mmHg and 6.2 +/- 1.6 L/min, mean +/- s.d.) were significantly lower than in both Pugh's B (16.8 +/- 4.3 mmHg and 7.3 +/- 2.1 L/min) and Pugh's C (18.8 +/- 5.5 mmHg and 7.4 +/- 2.3 L/min) patients (P < 0.01), respectively. In contrast, the systemic vascular resistance in Pugh's A patients (1232 +/- 369 dyn/s per cm5) was significantly higher than in both Pugh's B (1016 +/- 345 dyn/s per cm5) and Pugh's C (935 +/- 234 dyn/s per cm5) patients (P < 0.01), respectively. Additionally, not only was there a positive correlation found between Pugh's score and cardiac output and hepatic venous pressure gradient, but a negative correlation was found between Pugh's score and systemic vascular resistance. It was also confirmed that the degree of portal hypertension and the hyperdynamic circulation were more severe in patients with ascites than in those without ascites. However, there were no statistically significant differences in hepatic venous pressure gradient among patients with F1, F2 and F3 esophageal varices (15.7 +/- 4.0, 17.0 +/- 4.8 and 18.0 +/- 4.8 mmHg, respectively). It is concluded that in those patients with cirrhosis, the severity of cirrhosis is closely related to the degree of the hyperkinetic circulatory state and portal hypertension.

Hyposensitivity to vasopressin in patients with hepatitis B-related cirrhosis during acute variceal hemorrhage.

It has been suggested that vasopressin given during hemorrhage may be less effective than when given during a stable state in a portal-hypertensive rat model. This study was designed to evaluate the hemodynamic response to vasopressin infusion in 25 HBsAg-positive cirrhotic patients. Nine patients had active variceal hemorrhage before vasopressin infusion, and the other 16 patients were in a stable condition at the time of infusion. The two groups of patients were similar in baseline values except that a higher heart rate was found in patients with hemorrhage (96 +/- 20 vs. 73 +/- 10 beats/min, mean +/- S.D., p less than 0.01). Thirty minutes after vasopressin infusion (0.66 units/min), hepatic venous pressure gradient significantly decreased in both bleeding and stable patients (from 21 +/- 9 to 18 +/- 9 mm Hg, p less than 0.05; and from 18 +/- 4 to 8 +/- 3 mm Hg, p less than 0.0001, respectively). However, the decrease of hepatic venous pressure gradient was less obvious in bleeding patients as compared with stable patients (4 +/- 3 vs. 9 +/- 2 mm Hg, p less than 0.0001). A significant reduction of hepatic venous pressure gradient after vasopressin infusion was found in five bleeding patients without shock (from a median of 16 mm Hg [range = 12 to 26] to 11 mm Hg [range = 6 to 18], p less than 0.05), but not in four bleeding patients with shock (from 28 [range = 15 to 36] to 25 [range = 18 to 33] mm Hg, p greater than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Systemic and portal haemodynamic changes following triglycyllysine vasopressin plus nitroglycerin administration in patients with hepatitis B-related cirrhosis.

We measured the haemodynamic changes following triglycyllysine vasopressin administration and after addition of nitroglycerin in twelve patients with portal hypertension due to hepatitis B-related cirrhosis. A bolus i.v. injection of triglycyllysine vasopressin at a dose of 2 mg reduced the hepatic venous pressure gradient from 18.5 +/- 3.7 (mean +/- S.D.) to 15.6 +/- 4.0 mmHg, p less than 0.001. However, the cardiac index decreased from 4.8 +/- 1.0 to 3.7 +/- 0.8 l/min m2, p less than 0.001; the heart rate decreased from 79 +/- 15 to 71 +/- 13, p less than 0.01; the right atrial pressure increased from 3.2 +/- 1.9 to 5.3 +/- 2.3 mmHg, p less than 0.001; the mean arterial pressure increased from 92 +/- 13 to 103 +/- 13 mmHg, p less than 0.05; and the systemic vascular resistance rose from 939 +/- 182 to 1367 +/- 310 dyn/s cm-5, p less than 0.001. Furthermore, both mean pulmonary arterial pressure and pulmonary capillary wedge pressure showed a significant increase following triglycyllysine vasopressin administration as compared with baseline values (p less than 0.005). The addition of sublingual nitroglycerin at a dose of 0.6 mg returned all the systemic haemodynamic parameters to baseline levels. On the other hand, nitroglycerin administration caused no further change in the hepatic venous pressure gradient. We concluded that although triglycyllysine vasopressin significantly reduced portal pressure in patients with hepatitis B-related cirrhosis, it produced untoward systemic haemodynamic changes similar to those seen with vasopressin. The addition of nitroglycerin improved the detrimental systemic haemodynamic effects produced by triglycyllysine vasopressin without further reducing the hepatic venous pressure gradient.

Effect of verapamil on splanchnic haemodynamics in a portal hypertensive rat model.

To elucidate the effects of verapamil on splanchnic haemodynamics in rats with portal hypertension, verapamil was given at a low dose (0.2 mg/kg) and a high dose (2 mg/kg) to the rat model after portal vein ligation. Approximately 10% decrease in arterial pressure was caused by the low dose of verapamil, with significant decreases in cardiac output and portal venous inflow as well as reduced portal pressure; these were all indicative of a rise in portal vascular resistance. In contrast, the marked fall in both arterial pressure and cardiac output in the high dose, accompanied by a significant decrease in the portal pressure and the unchanged portal venous inflow, suggested a reduction in portal vascular resistance. This study shows that the acute effects of verapamil on portal hypertension may vary with the dosage used. These results also demonstrate that, since the therapeutic efficacy and safety of verapamil is only in a very limited range of dose, caution should be taken in its clinical use in the treatment of cirrhosis with portal hypertension.

Effect of parathyroid hormone on portal pressure in portal hypertensive rats.

Conflicting results have been common in the pharmacological treatments of portal hypertension. In an attempt to seek better management of portal hypertension, we studied the effect of the synthetic parathyroid hormone (PTH) fragment, [bPTH-(1-34)], in portal hypertensive rats (partial portal vein ligation). PTH, 10 U/kg, administered via the jugular vein resulted in a reduction of both mean arterial blood pressure (MAP) and portal pressure (PP) to a similar extent (18.9% and 16.9%, respectively). A higher dose (40 U/kg) of PTH lowered the PP by 27.8% and MAP by 43.2%. Hemodynamic experiments, performed with labelled microspheres, demonstrated that PTH decreased the blood flow of the splanchnic and hepatic portal collateral vascular beds. To determine whether there is a direct vasodilatory effect on the venous vasculature, the effect of PTH on the isolated portal vein was examined. PTH was capable of inhibiting both spontaneous and drug (methacholine 10(-7) mol/l or KCl 40 mmol/l-induced contraction in a dose-dependent manner. Therefore, it can be assumed that some of the effect of PTH on portal pressure is due to a selective effect on the portal vein.

Effects of endothelin and vasopressin on portal pressure of rats.

Endothelin is a vasoconstrictor peptide which has recently been isolated and sequenced from the vascular endothelial cells. It was reported to increase blood pressure in vivo and produce a prolonged contraction with a slow onset in vitro. The purpose of this study was to investigate whether endothelin can lower the portal pressure as another endogenous vasoconstriction peptidevasopressin (AVP) can. Heart rate, systemic blood pressure, portal pressure, and portal vein blood flow were measured. Effects of endothelin on these parameters were compared with those of AVP. Endothelin 10(-10) mol/Kg significantly decreased all of the parameters mentioned. At the higher dose (5 x 10(-10) mol/Kg), however, the portal pressure and blood pressure were increased and portal vein blood flow was unchanged. On the other hand, AVP decreased the portal pressure and portal vein blood flow but elevated the systemic blood pressure. In vitro experiments revealed that endothelin contracted both tail artery and portal vein of rat and vasopressin contracted only tail artery. We concluded that although both are endogenous vasoconstricting peptides, endothelin and AVP affect differently on arterial and venous vascular beds as well as on portal pressure.

Comparison between portal vein pressure and wedged hepatic vein pressure in hepatitis B-related cirrhosis.

Portal vein pressure and wedged hepatic vein pressure were measured simultaneously in 21 patients with hepatitis B-related cirrhosis of the liver and were compared to pressure measured in six patients with idiopathic portal hypertension. No significant difference in the portal venous pressure gradient was found between patients with cirrhosis and those with idiopathic portal hypertension (17.3 +/- 4.3 mmHg (mean +/- S.D.) vs. 19.7 +/- 3.1 mmHg, P greater than 0.05). However, the difference between the portal and the hepatic venous pressure gradient was significantly smaller in patients with cirrhosis than in idiopathic portal hypertension patients (1.3 +/- 1.7 vs. 10.8 +/- 2.1 mmHg, P less than 0.001). An excellent correlation was found between portal vein pressure and wedged hepatic vein pressure in hepatitis B-related cirrhosis (r = 0.94, P less than 0.001). There was no linear relationship between the portal venous pressure gradient and varix size or bleeding episodes. We concluded that a close agreement existed between portal vein pressure and wedged hepatic vein pressure in hepatitis B-related liver cirrhosis. Therefore, measurement of wedged hepatic vein pressure reliably reflects portal vein pressure in these patients.

Lack of effects of isosorbide-5-mononitrate on hepatic hemodynamics in HBsAg-positive cirrhosis.

We conducted a randomized controlled hemodynamic study to evaluate the effect of placebo and 20 mg isosorbide-5-mononitrate, a long-acting organic nitrate, in 19 patients with HBsAg-positive cirrhosis by the simultaneous measurement of portal venous pressure and wedged hepatic venous pressure. Baseline values for the two groups were similar. One hour after oral administration of 20 mg isosorbide-5-mononitrate in 10 patients, mean arterial pressure, mean pulmonary arterial pressure and pulmonary capillary wedge pressure significantly decreased from 92 +/- 13 (mean +/- S.D.) to 82 +/- 14 mmHg, from 12.9 +/- 4.5 to 9.3 +/- 2.4 mmHg and from 6.9 +/- 3.4 to 4.3 +/- 1.8 mmHg, respectively. However, both portal venous pressure gradient (from 18.1 +/- 3.6 to 17.5 +/- 3.0 mmHg) and hepatic venous pressure gradient (from 17.8 +/- 5.2 to 16.6 +/- 5.3 mmHg) remained unchanged during the study. In six patients who received 20 mg isosorbide-5-mononitrate twice daily for 7 days, hepatic venous pressure gradient remained unaltered as compared to basal and 1-hr values. There was no significant change in cardiac index, heart rate or systemic vascular resistance in either immediate (1-hr) or delayed (7-day) studies. Three patients (30%) developed mild headache or dizziness and two patients (20%) demonstrated systolic hypotension (less than mmHg) during the immediate study. This study shows that isosorbide-5-mononitrate appears to have no effect in treating portal hypertension in patients with HBsAg-positive cirrhosis. In addition, the isosorbide-5-mononitrate may affect the systemic circulation more than the portal circulation.

An animal study of portal hypertension.

For the purpose of elucidation the mechanism of portal venous resistance and portal venous blood flow in maintaining an elevated portal hypertension. The splanchnic and systemic hemodynamics were evaluated in portal hypertensive rat model, which is induced by partial portal vein ligation (PVL). Organ blood flow and portal-systemic shunting were measured by radio-active microsphere techniques. In this study all the PVL rats had higher mean portal venous pressure (15.2 +/- 1.6 mmHg) when compared to the Sham-operation control rats (5.3 +/- 1.2 mmHg). Furthermore, portal systemic shunting was significantly higher in the 14th day PVL rats (87.2 +/- 3.6%) than control rats (0.3 +/- 0.1%) (p less than 0.05). There was a rapid increase in portal venous inflow from the 4th day (6.1 +/- 0.8 vs 4.2 +/- 0.7 ml/min/100 gm BW, p less than 0.05) in the PVL rats than in control rats. However, the total peripheral resistance and splanchnic arterial resistance were reduced in the 14th PVL rats than control rats. The Cardiac index was much higher in the 14th PVL rats than control rats. Thus our results demonstrate that portal hypertension is maintained by a hyperdynamic portal venous inflow. This model is reproducible for us to study portal hypertension within a short period of time.

The influence of verapamil and nifedipine on hepatic indocyanine green clearance in patients with HBsAg-positive cirrhosis and ascites.

The influence of verapamil and nifedipine on hepatic indocyanine green kinetics was studied in 12 patients with HBsAg-positive cirrhosis and ascites. Hepatic clearance and its two biologic determinants, hepatic blood flow and metabolic activity (intrinsic clearance [maximum velocity/metabolite elimination rate constant, or Vmax/km]), were determined from hepatic indocyanine green elimination at steady state in patients with cirrhosis. Acute intravenous administration 10 mg verapamil significantly increased the hepatic indocyanine green blood flow (p less than 0.05), but significantly decreased the hepatic clearance (p less than 0.05), extraction ratio (p less than 0.05) and Vmax/km (p less than 0.05). However, acute sublingual administration of 10 mg nifedipine resulted in no significant change in any parameters of hepatic elimination function. These results show that verapamil, but not nifedipine, might impair the transhepatic extraction activity of hepatocytes in patients with HBsAg-positive cirrhosis and ascites.

Huge splenic artery aneurysm after portocaval shunt.

A 64-year-old man with cirrhosis of the liver had a palpable, pulsatile palm-size mass over the upper abdomen. Splenic artery aneurysm was diagnosed by sonography, computed tomography scan, and celiac angiography. Operative findings showed a huge splenic artery aneurysm (20 X 30 X 20 cm) over the middle portion of the splenic artery. Such a huge splenic artery aneurysm may develop because changes in splenic circulatory dynamics after a portocaval shunt, resulting in compression of the splenic vein and congestive splenomegaly.

Effects of verapamil on estimated hepatic blood flow in patients with HBsAg-positive cirrhosis.

Acute and chronic effect of verapamil on estimated hepatic blood flow were investigated in 12 patients with HBsAg-positive cirrhosis and portal hypertension. Acute administration of verapamil results in a significant increase (8%) in estimated hepatic blood flow (p less than 0.05). However, after chronic continued administration of verapamil, the mean value of estimated hepatic blood flow remains unchanged vis-a-vis basal values. Acute and chronic use of verapamil significantly reduced the hepatic venous pressure gradient for about an average of 20% at 1 hr after drug administration (p less than 0.05) and 18% 2 weeks later (p less than 0.05). This drop was associated with a significant reduction in hepatic vascular resistance by 39% at 1 hr later and by 37% 2 weeks later. Furthermore, the drop in hepatic vascular resistance was independent of any verapamil-induced changes in systemic hemodynamics. Verapamil significantly increased the indocyanine green plasma clearance and extraction ratio after acute or chronic use of the drug. We conclude that in patients with HBsAg-positive cirrhosis, the mechanism of verapamil in reducing the hepatic venous pressure gradient is predominantly by inducing a drop in hepatic portal vascular resistance.

Lack of effects of nifedipine on hepatic hemodynamics in patients with HBsAg-positive cirrhosis.

The acute effects of Nifedipine on hepatic venous pressure gradient (HVPG) and estimated hepatic blood flow (EHBF) were investigated in six patients with HBsAg-positive cirrhosis and portal hypertension by simultaneous hepatic venous catheterization. The mean arterial pressure significantly decreased by 18% at 1 h after sublingual administration of 10 mg Nifedipine. Significant increases in heart rate (13%) and cardiac output (20%) were also demonstrated in our patients 1 h after administration of Nifedipine. However, there were no significant changes in HVPG and EHBF after Nifedipine. We conclude that in patients with HBsAg-positive cirrhosis who receive Nifedipine, EHBF is maintained despite a substantial change in systemic hemodynamics, and that Nifedipine is not effective in acutely reducing HVPG.