Effects of fish oil on cell proliferation and liver injury in an experimental model of acute hepatic injury induced by carbon tetrachloride.

OBJECTIVE: We aimed to investigate the effect of fish oil on the hepatic injury and cell cycle phases as well as cellular proliferation- regeneration in a rat model of acute hepatic injury induced by carbon tetrachloride. BACKGROUND: Compensatory cell proliferation and tissue regeneration occurs as an endogenous response following chemical damage to the liver and enable animals to over come the injury. Data related to effect of fish oil on liver injury induced by chemical hepatotoxicants are controversial. METHOD: 60 male Wistar-albino rats were fed either with a diet supplemented with 20% fish oil or standard rat feed for 2 weeks. After an overnight fast, rats in each group were administered either 1 ml/kg carbon tetrachloride or saline intraperitoneally. RESULTS: Fish oil enriched diet significantly enhanced the carbon tetrachloride - associated necroinflammatory damage, ballooning degeneration and the elevation of serum transaminases induced by carbon tetrachloride. Furthermore fish oil diet prevented cell proliferation, increased the proportion of cells in the G0/G1phase concomitant with a decrease in the proportion of cells in the S phase cells. CONCLUSION: Fish oil diet exacerbates the hepatic injury and prevents cell proliferation-regeneration in normal and injured liver cells. Suppression of tissue regeneration by fish oil may lead to progression of the hepatic injury (Tab. 3, Fig. 4, Ref. 31).

Prostaglandin E2 formation by rat gastroduodenal tissue following intragastric acid perfusion.

Rat gastroduodenal mucosa forms prostaglandin (PG) E2. However, little is known about regional differences in PGE2 formation or the effect of gastric hydrochloric acid (HC1) perfusion on regional PGE2 formation. In this study, the rats were divided into 3 groups. Group 1 received intravenous (i.v.), 1 Ml/h, and intragastric (i.g.), 8 ml/h, perfusions of saline simultaneously for 3 h. Group 2 received saline i.v. and 0.15 N HC1 i.g., 8 ml/h. Group 3 was injected with a bolus of asprin (ASA), 60 mg/kg, followed by ASA, 40 mg/kg/h i.v., and 0.15 N HC1 i.g.. The gastric aspirates were analyzed for volume and pH. Segments of gastroduodenal tissue from the fundus, corpus, antrum, and duodenum were minced and then incubated in 1 ml of 5 mM Tris buffer, pH 8.4, for 30 sec with mixing; the incubate was assayed for PGE2 by radioimmunoassay. Intragastric HC1 decreased the pH of aspirate without producing gastric mucosal lesions. However, when combined with i.v. ASA, ulcer formation was present in all animals (p less than 0.05). PGE2 was formed by isolated tissue from four different gastroduodenal regions. The duodenum formed significantly greater amounts than the fundus, antrum, or corpus, which were similar. Intragastric HC1 produced a trend toward increased PGE2 formation (pmol PGE2/mg tissue) in the fundus, 143 +/- 36 to 237 +/- 57; corpus, 87 +/- 13 to 200 +/- 57; antrum, 157 +/- 28 to 224 +/- 65; and duodenum, 235 +/- 56 to 338 +/- 51. However, statistical significance was not reached.

Effect of dopamine on portal blood flow in cirrhotic patients.

OBJECTIVE: The effects of dopamine infusion on portal blood flow were examined in 12 cirrhotic patients (seven men, five women) in a Child-B group. METHODS: Dopamine was administered as an intravenous infusion (2 micrograms kg-1 min-1). RESULTS: At 0, 30 and 60 min, portal blood flow, left ventricular systolic and diastolic functions were evaluated using the pulsed doppler method. No significant difference was found between heart rate, blood pressure and parameters demonstrating left ventricular systolic and diastolic functions before and after dopamine infusions. Portal blood flow decreased significantly at 30 and 60 min. Portal blood flow fell from 1802 +/- 88 to 1339 +/- 50 ml min-1 (P < 0.001) at 30 min and to 1121 +/- 60 ml min-1 (P < 0.001) at 60 min. CONCLUSION: The reducing effects of dopamine on portal blood flow in cirrhotic patients were demonstrated by the pulsed doppler method, which is a noninvasive test.

Effect of verapamil on portal and splanchnic hemodynamics in patients with advanced posthepatitic cirrhosis using duplex Doppler ultrasound.

PURPOSE: To assess the effect of verapamil (80 mg) oral administration on portal and splanchnic hemodynamics in patients with advanced posthepatitic cirrhosis using duplex Doppler ultrasound (US). METHODS: Fourteen patients with post-hepatitic liver cirrhosis were included in the study. Duplex Doppler sonographic examinations were performed before, and 2-3 h after, 80 mg verapamil oral administration. Portal and splanchnic hemodynamics including vessel diameters (mm), mean flow velocities (cm/s), blood flows (ml/min), Doppler indices such as pulsatility and resistive indices (PI and RI), were investigated before and after verapamil administration. RESULTS: After verapamil administration; diameter of portal vein, splenic vein, and superior mesenteric artery (SMA) showed increase of 8%, 10%, and 7% (P < 0.05 to < 0.001), respectively. Increases of 20%, 38%, and 47% were found in blood flows (P < 0.05 to < 0.0001) with respect to the above vessels. Decreases of 17%, 10%, 11%, and 7% were found in SMA PI, SMA RI, splenic artery (SA) PI, and SA RI, respectively (P < 0.05 to < 0.0001). CONCLUSIONS: Verapamil appears to have splanchnic, portal, splenic, portocollateral and probably intrahepatic vasodilator effects in patients with advanced posthepatitic liver cirrhosis. Verapamil should be further investigated in the treatment of patients with advanced liver cirrhosis with prospective studies measuring portal and wedged hepatic pressure.

Measurement of gallbladder volume with ultrasonography in pregnant women.

Fasting and postprandial gallbladder volumes were investigated using ultrasonography in three groups (10 subjects in each) of healthy women: third trimester pregnant women, postpartum women up to 10 days after giving birth and nonpregnant controls. The scans were performed at 09:00 after a 12 h fast. After the basal measurement was taken, gallbladder volumes were rescanned in 15 min intervals for 60 mins. At the end of this period, all volunteers received a standard liquid test meal, and scans were performed again for 1 h. The mean basal gallbladder volume was 22.2+/-4.2 mL in the nonpregnant (control) group. In the third trimester group, the basal volume was 37.8+/-10.5 mL -70.5% higher than in the nonpregnant group (P<0.001). In the postpartum group, the mean basal volume was 37.9% lower (27.4+/-6.5 mL) than that of the third trimester group (P<0.02). This basal volume was 23.6% greater than that of the control group (P<0.05). After administration of a test meal, the postprandial gallbladder volumes decreased during the first few minutes compared with baseline values. The volumes decreased by 10.2% to 39.8% (23.5+/-7.3 to 34.0+/-10.2; P<0.01) in the third trimester group, by 14.9% to 43.2% (16.6+/-4.3 to 23.3+/-5.5; P<0.01, 0.001) in the postpartum group and by 19.2% to 51.6% (11.9+/-3.5 to 17.9+/-3.6; P<0.02, 0.05, 0.01, 0.001) in the control group. Postprandial mean gallbladder volumes of the third trimester (P<0. 02) and postpartum groups (P<0.02 to 0.01) were significantly different from those of the control group. In conclusion, incomplete emptying of the gallbladder after eating during the third trimester of pregnancy may contribute to cholesterol-gallstone formation, and pregnancy may thus increase the risk of gallstones.

Action of cisapride on gallbladder contraction in patients with diabetes mellitus.

BACKGROUND/AIMS: Gallbladder emptying abnormalities are common in patients with diabetes mellitus, and it has been hypothesized that they contribute to the increased incidence of gallbladder stones and biliary pain observed in these patients. Cisapride is a drug that exerts a prokinetic effect in both animals and humans. Recently, we demonstrated that cisapride decreased the fasting and post-prandial gallbladder volume in healthy subjects. Therefore, we investigated the action of cisapride on gallbladder contraction in diabetic patients. METHODOLOGY: Twenty diabetes mellitus patients and 20 healthy volunteers participated in this study. On the day of the study, ultrasonography was performed at 9 am, after 12 hours of fasting. After the basal measurement was obtained, the diabetic patients and healthy subjects received 10 mg cisapride or a placebo peroral. Two hours later, gallbladder volumes were rescanned by ultrasonography at 15-minute intervals for 60 minutes. RESULTS: The fasting gallbladder volume was 19.8 +/- 6.7 ml in the diabetic patients, and after the administration of cisapride, the gallbladder volume decreased by 32.2%-38.6% as compared to the baseline (p<0.02, 0.05, 0.01) and by 35.0%-45.8% as compared to the diabetic controls (p<0.02, 0.05, 0.001). In the healthy subjects, cisapride did not change the fasting mean gallbladder volume as compared to the baseline. After the administration of cisapride in the diabetic patients, the mean gallbladder volume decreased more than in the healthy subjects. The mean gallbladder volumes of the diabetic patients were between 12.1 +/- 4.2-13.4 +/- 4.2 ml. In the healthy volunteers, after the administration of cisapride, the volume was reduced by 1.9%-11.3% as compared to the healthy control group, but the volume changes of these two groups were not statistically significant. CONCLUSION: This study shows that the administration of cisapride causes gallbladder volume reduction in diabetic patients.

Effect of long-acting somatostatin analogue (octreotide, SMS 201-995) plus calcium channel blocker (verapamil) on gallbladder contraction.

BACKGROUND/AIMS: In this study we investigated the effect of the long-acting somatostatin analog octreotide (SMS 201-995) plus calcium channel blocker (Verapamil) on gallbladder contraction. METHODOLOGY: Fourty healthy volunteers participated in this study. Gallbladder volumes were measured by ultrasonography. After recording the baseline measurement, the volunteers received either saline (n:10), or SMS 201-995 100 B microgram subcutaneously (s.c.) (n:10) or verapamil 80 mg peroral (po) (n:10), or verapamil plus SMS 201-995 (n:10). Two hours later the gallbladder volumes were rescanned in 15 min intervals for 60 min. At the end all volunteers received standard liquid test meal (ensure 250 Cal/250 ml) and scans were again performed for one hour. RESULTS: The mean baseline gallbladder volume was 18.6 +/- 5.2 ml in all groups. The gallbladder volumes in the placebo group were 18.6 +/- 5.2 to 19.0 +/- 10.2 ml. In this group, after administration of test meal decreased the mean gallbladder volume to 14.3 +/- 7.5 to 8.4 +/- 5.8 ml, but these values were not significantly different from the baseline values. In the verapamil group the volumes increased from 18.6 +/- 5.2 to 28.5 +/- 9.7 to 30.8 +/- 11.6 ml. These values were significantly different from the baseline and the control group (p < 0.05). In this group, post-prandial mean volumes decreased to baseline in 30 min, but these values were higher than in the placebo group (p < 0.01). Verapamil-induced fasting the gallbladder relaxation was totally abolished to the placebo value by SMS 201-995. In verapamil plus SMS 201-995 and SMS 201-995 alone groups, the fasting and post-prandial volumes did not change when compared to the baseline value, but post-prandial volumes were higher than the placebo (p < 0.01). CONCLUSION: These results suggest that verapamil-induced gallbladder relaxation was totally abolished by SMS 201-995.

Effect of omeprazole on gallbladder contraction in humans.

BACKGROUND/AIMS: Omeprazole causes hypergastrinemia because of the effects of prolonged complete suppression of acid secretion and also gastrin has an excitatory effect on gallbladder contraction. Therefore, we investigated the meal-induced gallbladder emptying in healthy subjects receiving omeprazole and compared them to controls. METHODOLOGY: Twenty healthy volunteers participated in this study. Gallbladder volume was measured by ultrasonography. After basal measurement, the volunteers received saline intravenously (i.v.) 2 cc (no:10) or omeprazole 20 mg i.v. (no:10). After 15 min the gallbladder volume was scanned at 15 min intervals for 60 min for each of the subjects. At the end of the period, all the subjects received a standard test meal (ensure 250 cal/250 mL), after 1 hour the gallbladder volumes were rescanned at 15 min periods for 60 min. RESULTS: Mean gallbladder volume in the omeprazole group was not significantly different during a 45 min period as compared to the baseline value. The residual gallbladder volume at the end of the 15th minute (43.9 +/- 5.6 mL), 30th minute (45.4 +/- 5.9 mL), 45th minute (40.5 +/- 6.1 mL) and 60th minute (40.5 +/- 6.1 mL) showed no significant differences in both the omeprazole group and the controls. Mean gallbladder volumes of both groups after meal intake were significantly lower during the 1-hour period as compared to the baseline value (P < 0.05). The mean volumes did not show any significant differences between the omeprazole group and the control subjects. CONCLUSIONS: Omeprazole did not change the gallbladder volume during fasting and the postprandial period as compared to the control group.

Action of somatostatin analogue (octreotide) on experimental hepatic encephalopathy in rats.

BACKGROUND/AIMS: We investigated the effect of a somatostatin analogue (octreotide) on hepatic encephalopathy in a rat model. Fulminant hepatic failure was induced by thioacetamide twice daily for 3 consecutive days. METHODOLOGY: Animals with hepatic encephalopathy grade III were divided into 2 groups. The groups received saline (control) or octreotide. In both groups the distance traveled in the open field activity, neurological score and mortality time were evaluated before and after the treatment. RESULTS: In the control group the motor activity was 13.7 +/- 6.4 and 12.9 +/- 5.5 cm/10 min, the neurological score was 8.4 +/- 0.9 and 8.5 +/- 1.3 before and after the treatment, respectively. In the octreotide group the motor activity was 11.4 +/- 5.0 and 10.4 +/- 3.5 cm/10 min, the neurological score was 8.8 +/- 1.5 and 8.6 +/- 0.9 before and after the treatment, respectively. Mortality times in the saline and octreotide group were 76.1 +/- 28.1 and 89.7 +/- 46.5 min, respectively. All parameters of this study were statistically not significant. CONCLUSIONS: This study demonstrated that somatostatin analogue, octreotide does not effect hepatic encephalopathy in an experimental rat model.

Does nimesulide induce gastric mucosal damage? "A double-blind randomized placebo-controlled trial".

BACKGROUND/AIMS: In this study, it was aimed to examine the effect of nimesulide, a selective inhibitor of cox-2 enzyme, to the gastric mucosa and to correlate its effect with aspirin. METHODOLOGY: This study was planned as double-blind, randomized and placebo-controlled. Mean age of voluntary persons (n = 32) was 42.3 +/- 2.7. Divided into 3 groups of volunteers were given randomized placebo (n = 10), aspirin (n = 10) (500 mg aspirin, Bayer) and nimesulide (n = 12) (100 mg mesulid, Pfizer) with 50 mL of water after 12 hours fasting period at 08.00 am. Gastroduodenoscopy was performed to the volunteers 3 hours after each therapy. RESULTS: Endoscopic scores of groups were; placebo: 0.20 +/- 0.13, aspirin: 2.8 +/- 0.46, nimesulide: 1.41 +/- 0.51. Lesion scores both in the aspirin group when compared with nimesulide and placebo groups (P < 0.00002, < 0.03), and in the nimesulide group when compared with the placebo group (P < 0.01) were significantly high. The positivity of Helicobacter pylori of groups was found; 67% in placebo, 72% in aspirin, 71% in nimesulide and there was no statistically significant difference in the groups. CONCLUSIONS: It was shown that nimesulide causes significantly serious gastric mucosal lesion when compared with placebo. The lesion score of nimesulide was found less than aspirin. According to the findings, nimesulide should be given carefully just as other analgesics due to the probability of causing gastric lesion.

Cola drinks consumption and oesophagitis.

For oesophageal epithelial changes to develop from gastro-oesophageal reflux disease (GORD), the character of the refluxate must be acid enough to cause injury. Experimentally, copious perfusion of the oesophagus with weak acid is quite harmless. However, hydrochloric acid alone with a pH below 3.0 may cause oesophageal injury. Cola drinks are strongly acidic (pH 2.5). This study analyses the influence of and possible interaction between cola consumption and oesophagitis. Twenty rats were divided into two groups of 10. The animals received saline (pH 7.0) or cola (pH 2.6) per OS with 24 h free access to these solutions. After the experiment the oesophagus was dissected. The mucosa was macroscopically and histopathologically examined, and flow cytometric analysis was used to look for proliferative activity. The histopathological analysis showed that there is no difference between saline and cola. But the findings of cell cycle analysis showed that the effects of cola and saline in inducing oesophageal mucosal damage are different. In the cola group the values were G0/G1, 7.33 +/- 2.88; S, 29.88 +/- 2.88; G2/M, 0.10 +/- 0.01; PI (proliferative-regenerative index), 29.76 +/- 2.88. The rat cell population g0/g1 phases were found to be low (p < 0.01), and the cell population S and PI phases were found to be significantly elevated compared with the control group (p < 0.01). (G0/G1, 79.30 +/- 5.97; S, 16.06 +/- 8.27; G2/M, 4.66 +/- 4.03; PI, 20.03 +/- 6.01). These results were reflected in the proliferative index, which is used as a measure of the regeneration index. The data show that cola has proliferative and regenerative effects on the oesophageal mucosa, and it is possible that its regenerative effect is caused as a result of an irritant effect.

Treatment of migraine attacks with a long-acting somatostatin analogue (octreotide, SMS 201-995).

Long-acting somatostatin analogue (SMS 201-995) inhibits serotonin, bradykinin, prostaglandins, substance P, and vasoactive intestinal peptide, which may be involved in migraine. We therefore decided to test the efficacy of SMS 201-995 in relieving the pain of acute migraine attacks. Headache relief was defined as a reduction in severity from grade 3 or 2 (severe or moderate) to 1 or 0 (mild or none). Patients experiencing migraine attacks were evaluated clinically. A double-blind parallel group trial was performed in which patients randomly received either a subcutaneous injection of placebo (saline) or SMS 201-995 (100 micrograms). SMS 201-995 was significantly more effective than placebo in reducing headache grade at 2 h (1.5 +/- 0.6 vs 2.2 +/- 0.7; p < 0.01), 4 h (1.5 +/- 0.6 vs 2.1 +/- 0.8; p < 0.05) and 6 h (0.8 +/- 0.9 vs 2.1 +/- 0.8; p < 0.001) after the initiation of treatment. By 6 h, apparent headache relief (reduction in severity from grade 3 or 2 to 1 or 0) was experienced in 76.5% of SMS 201-995 treated patients and 25% of the placebo-treated group. Headache relief was significantly better in patients taking SMS 201-995 (p < 0.02). Furthermore, none of the patients became pain-free (headache grade 0) on placebo, while significantly more patients (47%) were pain-free on SMS 201-995 at 6 h (p < 0.01). Headache improvement started significantly earlier in those patients treated with SMS 201-995 than with placebo. SMS 201-995 significantly improves the pain of migraine attacks, 2 h after the beginning of treatment. Additionally, we observed no side effects of SMS 201-995. We therefore conclude that a single dose of 100 micrograms given subcutaneously is an effective and well-tolerated agent for the treatment of migraine attacks.

Inhibition of penile erection in rats by a long-acting somatostatin analogue, octreotide (SMS 201-995).

OBJECTIVE: To assess the effect of a new somatostatin analogue (SMS 201-995, octreotide) on erectile function in rats. MATERIALS AND METHODS: Animals were fasted and anaesthetized intraperitoneally with pentobarbital. A cannula was placed in the trachea and the femoral vein cannulated for intravenous infusion. The hypogastric and pelvic nerve, major pelvic ganglion, and the nerve fibres to the lower genitourinary tract were identified. In 20 animals, these nerves were stimulated unilaterally using bipolar silver-wire electrodes; the stimulation was repeated every 15 min for 1 h. Twenty animals were divided into two equal groups; after measuring penile erection to obtain basal values, the animals received either saline or 50 micrograms SMS 201-995 over 1 h and 30 min later, the stimulation was repeated. RESULTS: After administering SMS 201-995 or saline, the levels of penile erection reduced linearly in both groups, but SMS 201-995 caused a greater decrease than in the control group (P < 0.05) and from baseline (P < 0.01) at all times. CONCLUSION: SMS 201-995 inhibits penile erection in rats and the systems may serve as an in vivo animal model for further investigation.

The inhibiting effect of cola on gastric mucosal cell cycle proliferation in humans.

BACKGROUND: Acidic beverages may be involved in regulating the cell proliferation of the gastric mucosa. We therefore analyzed the interaction of Coca-Cola consumption and gastric mucosal proliferation by means of flow cytometry. METHODS: Sixteen healthy students agreed to participate in this study. All volunteers underwent an oesophagogastroduodenoscopy after a 12-h overnight fast. Endoscopic changes in the gastric mucosa were determined quantitatively. One day later, after a 12-h overnight fast, all volunteers received standard Coca-Cola (200 ml, pH 2.6, 4 degrees C). One hour later all volunteers again underwent oesophagogastroduodenoscopy, to measure gastric mucosal damage. During both the first and the second endoscopy at least four biopsy specimens were taken from the antrum for flow cytometric analysis. RESULTS: The endoscopic analysis showed that there was no difference before and after Coca-Cola consumption. However, the flow cytometric analysis showed that Coca-Cola inhibited the proliferation index and the S phase. Before Coca-Cola consumption G0/G1: 60 (57-62), G2/M: 0.6 (0.2-1), S: 40 (37-42), and PI: 0.40 (0.38-0.43) and after Coca-Cola consumption G0/G1: 70 (60-73), G2/M: 1.9 (1.2-2.5), S: 28 (26-32), and PI: 0.30 (0.27-0.34) the cell population G0/G1 and G2/M phases were significantly increased (P < 0.0001, 0.0003), and the cell population S and PI phases were significantly low compared with the pre-consumption data (P < 0.0002, 0.0001). CONCLUSION: The cell cycle analysis reflects that Coca-Cola inhibits a crucial event in the cell cycle occurring at the G1/S border.

Effect of cisapride on portal haemodynamics in patients with liver cirrhosis using duplex Doppler ultrasonography.

PURPOSE: Cisapride, a benzimide derivative, is a gastrointestinal prokinetic agent without dopamine-antagonistic or cholinomimetic effects. This study aims at assessing the effect of cisapride oral administration on portal flow in patients with advanced post hepatitic cirrhosis using duplex Doppler ultrasound (US). METHODS: A total of 12 patients with post-hepatitic liver cirrhosis were included in the study. Duplex Doppler sonographic examinations were performed before and after treatment. The subjects received 10 mg cisapride before starting the measurement procedure and then three times a day for 2 days. Portal haemodynamics including vessel diameters (mm), mean flow velocities (cm/s), blood flows (ml/min) were investigated. RESULTS: Mean portal vein diameters, mean portal flow velocity and portal blood flow volume showed decreases of 18.6, 22.1 and 43.6% (P<0.001), respectively. After cisapride administration the portal vein diameter did not change in two patients and the portal vein velocity did not change in three patients. No significant change was found in systolic blood pressure, diastolic blood pressure or pulse rate after the administration of cisapride. CONCLUSION: In this study, it was demonstrated that oral administration of cisapride results in a significant reduction of portal blood flow but there were no changes in heart rate or systolic pressure in patients with cirrhosis of the liver.

The effect of indomethacin on hepatitis B virus replication in chronic healthy carriers.

BACKGROUND: A chronic HBsAg carrier state, a major cause of viral spread in a community, is one of the consequences of hepatitis B virus (HBV) infection. Although successful immunization programs have been initiated to eliminate the virus, there is still a large number of people with HBV infection worldwide. This study was designed to investigate the effect of indomethacin treatment on HBV markers in humans, in comparison with a control group. METHODS: In total, 65 chronic 'healthy' HBV carriers were involved in the study. Patients were divided randomly into two groups. Group I (n = 42) received oral indomethacin 75 mg daily for 6 months. Group II (n = 23) acted as control. Patients in both groups were followed up for 6 months, during which laboratory tests, including viral parameters, were performed periodically. Liver biopsy was done in 17 patients (11/42 of the indomethacin group and 6/23 of the control group). RESULTS: All liver biopsies showed grade 0-2 and stage 0-1 HBV in both groups (P > 0.05). HBsAg positivity did not change in any patient in either group. Five patients who had positive HBeAg in group I became negative 4 months later, while patients in group II continued to be positive at 6 months (P < 0.001). Similarly, all patients receiving indomethacin exhibited a total anti-HBeAg immunoglobulin response at 6 months, while the control group remained the same during this period (P < 0.05). HBV DNA, as detected by polymerase chain reaction in 20/22 (91%), was negative in group I at the end of 6 months. No change was observed in group II (P = 0.007). CONCLUSIONS: Although no biochemical analyses were performed on prostaglandins in the present study, the results suggest that the prostaglandin pathway may be involved in the pathogenesis of the immune response against HBV, and that the suppression of viral replication is achieved as indicated by the disappearance of HBeAg and HBV DNA in healthy chronic HBV carriers.