Clinical trial: extended treatment duration of peginterferon-alpha2b plus ribavirin for 72 and 96 weeks in hepatitis C genotype 1-infected late responders.

BACKGROUND: The benefits of prolonging peginterferon and ribavirin after 48 weeks of treatment to maximize sustained virological responses (SVR) in hepatitis C virus (HCV) genotype 1-infected patients remain to be understood. AIM: To investigate whether extended treatment longer than 72 weeks may be superior to 72-week treatment. METHODS: A total of 120 treatment-naïve or retreated patients with HCV genotype 1 were treated with peginterferon-alpha-2b (1.5 microg/kg/week) plus weight-based ribavirin. We had 34 late responders, in whom HCV RNA first became undetectable at week 12-48, and randomized them into three groups receiving standard-dose peginterferon-alpha-2b plus low-dose ribavirin (200 mg/day) for extended 24 weeks (group A), receiving low-dose peginterferon-alpha-2b (0.75 microg/kg/week) plus low-dose ribavirin for extended 48 weeks (group B) or no extended treatment (group C), and evaluated the outcome according to their virological response. RESULTS: Multivariate analysis showed that the treatment for 96 weeks was identified as a significant, independent factor associated with SVR in HCV genotype 1-infected late responders in comparison with group A [odds ratio (OR), 10.002; P = 0.080] and group C (OR, 17.748; P = 0.025). CONCLUSION: Extending the treatment duration from 48 weeks to 96 weeks improves SVR rates in genotype 1-infected patients with late virological response to peginterferon-alpha-2b and ribavirin.

Can endoscopic papillary balloon dilation really preserve sphincter of Oddi function?

BACKGROUND: Endoscopic papillary balloon dilation (EPBD) is assumed to preserve sphincter of Oddi function because it causes little trauma to the papilla. However, few studies have addressed this issue specifically. In this study, we investigated whether EPBD can preserve sphincter function, and evaluated whether or not such preservation has clinical significance. METHODS: Seventy patients with common bile duct (CBD) stones were randomly assigned to EPBD or endoscopic sphincterotomy (EST). Sphincter of Oddi (SO) function was measured by endoscopic manometry before, one week after, and one year after treatment. Incidence of pneumobilia and later complications were compared between the two groups at one year. Series manometric data were compared within each group and between the two groups. For a more detailed analysis of the cumulative incidence of later complications, retrospective cohorts were added to the study groups, giving a total number of 235 patients in the EPBD group and 126 in the EST group. RESULTS: Baseline characteristics did not differ significantly between the 35 EPBD and 35 EST patients. CBD stones were discharged successfully in all cases. CBD pressure, SO basal and peak pressures, and contraction frequency decreased significantly at one week in both groups. The damage was more severe in the EST group, and SO contraction completely disappeared in 23 patients in this group. The incidence of pneumobilia was significantly lower in the EPBD group than in the EST group (p<0.01) whereas CBD stones recurred and cholecystitis appeared at a similar rate in both groups at one year. A complete series of manometric data up to one year was obtained in 55 patients; 28 in the post-EPBD and 27 in post-EST groups. In the post-EPBD group, SO basal and peak pressures significantly recovered at one year compared with data at one week but these measures still remained significantly lower than those before EPBD (p< 0.01). In the post-EST group, SO contraction did not recover even after one year. A Kaplan-Meier analysis of 235 EPBD and 126 EST patients for a median follow up of 37 months revealed significantly lower incidences of biliary complications such as recurrent CBD stones and cholangitis, and cholecystitis in the EPBD group than in the EST group (p<0.05). The risk of pneumobilia was also significantly lower in the EPBD group (p<0.01). CONCLUSIONS: Preservation of papillary function after EPBD was not complete but remained somewhat reduced. However, preservation was more successful with EPBD than with EST. Such preservation may be clinically beneficial for the prevention of later complications.

Therapeutic effect of balloon-occluded retrograde transvenous obliteration on portal-systemic encephalopathy in patients with liver cirrhosis.

OBJECTIVE: Balloon-occluded retrograde transvenous obliteration (B-RTO) has recently been introduced as a new interventional modality to prevent fatal bleeding from solitary gastric varices. A large portal-systemic shunt including gastric varices also causes severe encephalopathy in some cirrhotic patients. In this study, we evaluated the effect of B-RTO as a candidate therapeutic method to treat chronic recurrent hepatic encephalopathy due mainly to a portal-systemic shunt. PATIENTS AND METHODS: Since July 1995, we experienced 43 cirrhotic patients with chronic reccurent hepatic encephalopathy. Among them, six patients had anigographically proven large (>1 cm in diameter) portal-systemic shunt, and received B-RTO. B-RTO was carried out only once using 5% ethanolamine oleate with iopamidole to obliterate the portal-systemic shunt for 30 minutes. The median observation period after B-RTO was 29 months (range 23-46 months). RESULTS: In all 6 patients, encephalopathy had disappeared after B-RTO, and the patients were free of encephalopathy during the following 6 months. B-RTO significantly reduced blood ammonia levels at one month, 3 months, and 6 months later, without affecting serum aspartate aminotransferase activity, total bilirubin and albumin concentrations, and plasma prothrombin time. Encephalopathy relapsed in 4 patients between 6 and 30 months. Additional B-RTO was required and effective in 2 of them. CONCLUSION: B-RTO is an effective treatment for chronic recurrent hepatic encephalopathy with an angiographically proven portal-systemic shunt.

Inflammatory pseudotumor of the liver with primary sclerosing cholangitis.

Inflammatory pseudotumor (IPT) of the liver is a rare benign variant of hepatic masses, and its exact etiology has not been elucidated. We report a case of IPT associated with primary sclerosing cholangitis (PSC). The patient was a 50-year-old man admitted to our hospital because of jaundice. Abdominal ultrasonography (US) and computed tomography showed multiple dilations of the intrahepatic bile ducts and multiple masses in the liver. On magnetic resonance imaging, the masses were slightly hypointense on T1-weighted images and slightly hyperintense on T2-weighted images. On T1-weighted images after the bolus infusion of Gd chelate, the masses had no contrast enhancement, and they were hypointense in the arterial phase and portal venous phase. However, they were slightly enhanced and became almost isointense relative to the surrounding normal liver parenchyma in the delayed phase. Endoscopic retrograde cholangiography demonstrated multiple irregular strictures and dilations of the intrahepatic bile ducts. Angiography demonstrated no abnormal findings, but, interestingly, subsequent dynamic CO2-enhanced US showed a strongly hyperechoic string, indicating that an artery had penetrated through the hypoechoic mass. A US-guided percutaneous needle biopsy revealed that the lesions were morphologically comparable to IPT. After cholangiography and microscopic analysis of the tumor, the final diagnosis was determined to be IPT of the liver with PSC. A number of previous reports have suggested a possible relationship between IPT and PSC, based on pathological findings. This report confirmed, based on clinical findings, that PSC is one of the causes of hepatic IPT.

Both insulin sensitivity and glucose sensitivity are impaired in patients with non-diabetic liver cirrhosis.

Background: Careful nutritional support is required in patients with liver cirrhosis due to their glucose intolerance. To elucidate the mechanism of glucose intolerance in cirrhotics, we measured insulin secretion, whole body insulin sensitivity (SI), and glucose sensitivity (SG) in non-diabetic cirrhotics.Methods: Eight patients with compensated cirrhosis who showed normal fasting blood glucose levels and non-diabetic curves on a 75 g oral glucose tolerance test participated in this study. Four normal volunteers were selected as controls. After an overnight fast, glucose was injected intravenously at 300 mg kg(-1) in 2 min followed 20 min later by intravenous insulin at 0.02 U kg(-1) in 5 min. Sequential blood samples were drawn from 20 min before the glucose injection to 3 h post-injection, and plasma glucose and insulin levels were determined. Plasma glucose and insulin disappearance curves were analyzed using the minimal compartment model, and kinetic parameters, including glucose clearance (KG), insulin secretion, SI and SG, were estimated.Results: KG was slower in cirrhosis than in controls, although not significant (P=0.051). Insulin secretion was not different between the two groups. However, SI was significantly lower in cirrhotics (0.814x10(-4) min(-1) pM(-1); 0.572-1.403x10(-4) min(-1) pM(-1)) as compared to controls (1.643x10(-4) min(-1) pM(-1); 0.678-2.085x10(-4) min(-1) pM(-1)) (P=0.029). SG was also lower in the cirrhosis (0.0154 min(-1); 0.0071-0.0208 min(-1)) than in the control group (0.0211 min(-1); 0.0184-0.0260 min(-1)) (P=0.026).Conclusion: Both SI and SG are already impaired in non-diabetic cirrhotic patients even when KG is minimally delayed and insulin secretion has not yet been affected.

Elevated intracellular IFN-gamma levels in circulating CD8+ lymphocytes in patients with fulminant hepatitis.

BACKGROUND/AIMS: Fulminant hepatitis usually takes a rapidly progressive course, terminating in death within a short period. Experimental studies have demonstrated that immunological mechanisms play an important role, especially those involving virus-specific CD8+ cytotoxic T lymphocytes and their production of interferon-gamma (IFN-gamma). However, there are no immunological markers for prediction of the development of fulminant hepatitis in man. METHODS: Peripheral blood lymphocytes from four patients with fulminant hepatitis, six with acute hepatitis and 11 healthy volunteers as normal controls were analyzed. Intracellular IFN-gamma production in both CD8 positive and negative T lymphocytes was assessed by flow cytometry. RESULTS: Populations of CD8+ IFN-gamma+ T lymphocytes were significantly increased in patients with fulminant hepatitis, as compared with those with acute hepatitis and normal controls. Production of IFN-gamma in CD8+ T lymphocytes of patients with fulminant hepatitis was also elevated, furthermore significantly correlating with the prothrombin time (r=-0.64, p<0.01). CONCLUSIONS: The capacity for IFN-gamma production by CD8+ lymphocytes is up-regulated in fulminant hepatitis, and this may be important for the development of fulminant hepatitis.

Endoscopic papillary balloon dilatation for common bile duct stones: efficacy of combination with extracorporeal shockwave lithotripsy for large stones.

BACKGROUND: Endoscopic papillary balloon dilatation (EPBD) is generally considered a safe and effective technique for removal of common bile duct (CBD) stones. However, some reports have prompted concern about the risk of pancreatitis following the procedure, and it seems to be more difficult and to require adjunctive procedures more frequently in patients with large stones. AIMS: To analyse the factors influencing pancreatitis after the procedure, and to examine which is the more suitable adjunct for treating large stones, mechanical lithotripsy (ML) or extracorporeal shockwave lithotripsy (ESWL). PATIENTS AND METHODS: EPBD was performed in 92 patients, including 40 with large stones (> or = 12 mm). These 40 patients were randomly assigned to two groups receiving ML or ESWL to fragment stones (20 patients each). RESULTS: Complete ductal clearance was obtained in all 92 patients. Significant elevation of the serum amylase level compared with the prior value (> 300 IU/l) was observed in 26 (28%), and eight (8.7%) developed clinical pancreatitis. To assess the influence of various factors on the amylase level, multivariate analysis was used. The number of stones and the time required for treatment had a significant influence on the incidence of increased amylase level (P < 0.05), and ML also significantly increased it (P < 0.05). On the other hand, the amylase level remained low in the ESWL group. ML caused elevation of amylase level in 11 patients (55%), while three (15%) had elevation after ESWL. CONCLUSIONS: In patients with multiple stones, elevation of the amylase level is more frequent. This seems to be because repeated cannulation and much time is required for treatment. In patients with large stones, the rate was also high if ML was used, but was low when ESWL was used. ESWL may reduce the incidence of pancreatitis.

Usefulness of novel imaging modalities in diagnosis of focal nodular hyperplasia of the liver.

A 17-year-old woman was admitted because of a liver tumor found incidentally by ultrasonography. Liver function was normal and there were no markers of hepatitis viruses or malignancy. Abdominal ultrasonography, computed tomography (CT), and magnetic resonance imaging revealed a mass (2 cm in diameter) in the lateral segment of the left lobe of the liver. The lesion was not detected by hepatic arteriography. However, dynamic CT with fast scanning and dynamic CO2-enhanced ultrasonography demonstrated initial central enhancement of the mass followed by centrifugal spread of enhancement to the periphery. Color Doppler flow imaging detected a central color spot, shown to be an artery by a pulsed Doppler spectrum analysis. Fine-needle biopsy confirmed a diagnosis of focal nodular hyperplasia. Dynamic CT with fast scanning, dynamic CO2-enhanced ultrasonography, and color Doppler flow imaging were useful in detecting the vascular pattern specific to focal nodular hyperplasia. Investigation of further cases with these novel imaging modalities should help to establish a comprehensive diagnostic procedure and thus avoid unnecessary surgery for focal nodular hyperplasia, which is a completely benign lesion.

Extracorporeal shockwave lithotripsy of common bile duct stones without preliminary endoscopic sphincterotomy.

BACKGROUND: Endoscopic sphincterotomy (EST) is now a standard procedure for common bile duct stones. It is less invasive than surgical treatment and is well established, but complications such as bleeding and perforation occasionally occur. We have been investigating the safest and most useful method of preserving the papilla of Vater. In the present study we evaluated the effectiveness and safety of extracorporeal shock wave lithotripsy (ESWL) for common bile duct stones without preliminary EST. METHODS: From May 1992 to May 1995 ESWL was performed on 52 patients with common bile duct stones at our hospital. In all 52 patients a nasobiliary tube was inserted endoscopically, without preliminary EST, and ESWL was performed. RESULTS: Fragmentation and subsequent complete clearance of stones was achieved in 35 patients (67.3%), and no additional treatment was necessary. In 17 patients (25.0%) fragmentation was not achieved, so EST and endoscopic extraction were performed, and the stones were cleared completely. None of the patients had major complications with clinical sequelae. We compared the completely cleared group and the failed group, to assess the influence of various factors. Our findings indicated that smaller, 'floating' stones responded more favorably to ESWL. When the largest stone was < 15 mm in diameter and the stone index (diameter of common bile duct/diameter of stone) was > 1.0, the success rate was very high 25 of 27 = 92.6%). CONCLUSIONS: This treatment offers several advantages because it is less invasive, has few complications, and can preserve the papilla of Vater. This method is especially suitable for patients with smaller, floating stones.

Prevention of second primary tumors by an acyclic retinoid, polyprenoic acid, in patients with hepatocellular carcinoma. Hepatoma Prevention Study Group.

BACKGROUND: In patients with hepatocellular carcinoma (hepatoma), the rate of recurrent and second primary hepatomas is high despite surgical resection and percutaneous ethanol-injection therapy. We developed an acyclic retinoid, polyprenoic acid, that inhibits hepatocarcinogenesis in the laboratory and induces differentiation and apoptosis in cell lines derived from human hepatoma. In a randomized, controlled study, we tested whether the compound reduced the incidence of recurrent and second primary hepatomas after curative treatment. METHODS: We prospectively studied 89 patients who were free of disease after surgical resection of a primary hepatoma or the percutaneous injection of ethanol. We randomly assigned the patients to receive either polyprenoic acid (600 mg daily) or placebo for 12 months. We studied the remnant liver by ultrasonography every three months after randomization. The primary end point of the study was the appearance of a histologically confirmed recurrent or new hepatoma. RESULTS: Treatment with polyprenoic acid significantly reduced the incidence of recurrent or new hepatomas. After a median follow-up of 38 months, 12 patients in the polyprenoic acid group (27 percent) had recurrent or new hepatomas as compared with 22 patients in the placebo group (49 percent, P = 0.04). The most striking difference was in the groups that had second primary hepatomas--7 in the group receiving polyprenoic acid as compared with 20 in the placebo group (P = 0.04 by the log-rank test). Cox proportional-hazards analysis demonstrated that as an independent factor, polyprenoic acid reduced the occurrence of second primary hepatomas (adjusted relative risk, 0.31; 95 percent confidence interval, 0.12 to 0.78). CONCLUSIONS: Oral polyprenoic acid prevents second primary hepatomas after surgical resection of the original tumor or the percutaneous injection of ethanol.

Molecular cloning and cDNA sequencing of endoxyloglucan transferase, a novel class of glycosyltransferase that mediates molecular grafting between matrix polysaccharides in plant cell walls.

Endoxyloglucan transferase is a novel class of glycosyltransferase recently purified from Vigna angularis (Nishitani, K,, and Tominaga, R. (1992) J. Biol. Chem. 267, 21058-21064). This enzyme is the first transferase identified that catalyzes molecular grafting between polysaccharide cross-links in the cell wall matrix and participates in reconstruction of the network structure in the cell wall. Based on the NH2-terminal amino acid sequence information of the purified transferase, we have here cloned and sequenced cDNAs derived from five different plant species, V. angularis, Triticum aestivum, Arabidopsis thaliana, Lycopersicon esculentum, and Glycine max. In the five plant species, the amino acid sequence of the mature proteins is conserved in the range of 71-90% throughout their length. The consensus sequence for N-linked glycosylation, and four cysteine residues are all conserved in the five species. Thus, the endoxyloglucan transferase protein is ubiquitous among higher plants. The highly conserved DNA sequence will serve as a promising tool for exploring the molecular process by which cell wall construction, and hence cell growth, is regulated.

Two cases of endoscopically identified esophageal cancer of the superficial-slightly depressed type.

We experienced two cases of superficial type esophageal cancer. Case 1 was a 72-year-old man in whom endoscopic examination revealed a slightly protruded, partially reddened and faded area of irregular shape corresponding to 0-IIa + IIc (slightly depressed type) of the endoscopic classification of esophageal cancers. Macroscopically, it was a superficial, ill-defined and non-cicatrized solitary tumor measuring 2.5 x 2.4 cm in size. Histologically it was a monofocal semidifferentiated squamous cell carcinoma of a swelling type of stage 0. Case 2 was 55-year-old man. Endoscopic examination disclosed an almost roundish, smooth-surfaced, flat and dull red area corresponding to IIc (slightly depressed type). Macroscopically it was a superficial, semidefined and non-cicatrized solitary tumor measuring 1.0 x 1.0 cm in size. Histologically it was a monofocal, semidifferentiated squamous cell carcinoma of stage 0. To detect esophageal cancer at an early stage, the endoscopist needs to inspect the mucosa carefully. In case of males aged over 50, the endoscopist would be well advised to employ the dye-spraying method (Lugol staining method) at the endoscopic examination.

[Histopathological analysis of 73 autopsy cases of "acute-on-chronic" in Japan--influence of alcohol abuse on exacerbation of chronic liver disease].

Cases of acute exacerbation in chronic liver disease ("acute-on-chronic") in Japan were surveyed by questionnaire method since 1986 and 220 cases were collected. 73 pathological specimens of 102 cases which were autopsied were subjected to morphological analysis. The cases were divided according to causes of acute exacerbations: namely super-imposed viral infection or drugs (Group I), unknown causes or post immunosuppressant therapy (Group II), alcohol abuse (Group III), operation, digestive tract hemorrhage or post TAE etc, (Group IV). Area of hepatic necrosis was large and regeneration of hepatocytes were significantly strong in Group I and II compared with cases of Group IV. Regeneration was also inhibited in liver of habitual alcohol drinker. Significant difference was shown in cases of Group IV. Pathologically liver of 10 cases of Group III divided to florried cirrhosis (3 cases), alcoholic liver cirrhosis (4 cases) and alcoholic hepatitis combined with post hepatitic liver cirrhosis (3 cases, all HBV carriers).

[Enzymatic determination of a molar ratio of free branched-chain amino acids to tyrosine (BTR) and its clinical significance in plasma of patients with various liver diseases].

A molar ratio of free branched-chain amino acids to tyrosine (BTR) was determined in the plasma of patients with liver diseases using a new enzymatic method. In addition, clinical significance of BTR was studied by comparing particularly with that of Fischer's ratio (a molar ratio of branched-chain amino acids to aromatic amino acids (tyrosine+phenylalanine], which was obtained by conventional HPLC (Amino acid autoanalyzer, Hitachi 835). Following results were obtained: 1) Enzymatically determined branched-chain amino acids and tyrosine showed significant correlations with respective results obtained by HPLC (r = 0.937, 0.972). 2) Significant correlation was also found between enzymatically determined BTR and Fischer's ratio obtained by HPLC. Changes of BTR in clinical courses were found to be in parallel with those of Fischer's ratio. 3) BTR as well as Fischer's ratio correlated significantly with ICG R15, KICG, prothrombin time (%) and serum albumin level. 4) BTRs in patients with decompensated liver cirrhosis or with fulminant hepatitis were significantly lower than those in patients with acute or chronic hepatitis. In conclusion, new enzymatic assay of branched-chain amino acids and tyrosine as described here is quite simple method, and is also considered to be very useful parameter of the clinical conditions of patients with liver diseases, particularly representing the severity of liver diseases and the protein nutritional status.

Clinical significance of human hepatocyte growth factor in blood from patients with fulminant hepatic failure.

We have recently found the presence of human hepatocyte growth factor in sera of patients with fulminant hepatic failure and have purified human hepatocyte growth factor from plasma of a patient with fulminant hepatic failure. In this paper, we report the clinical significance of human hepatocyte growth factor in blood from patients with fulminant hepatic failure. The effect of sera or plasma from 17 patients with fulminant hepatic failure on liver cell growth was examined by use of adult rat hepatocytes in primary cultures. Sera or plasma from 16 of the 17 patients with fulminant hepatic failure stimulated DNA synthesis in hepatocytes more effectively than normal human serum. The mean growth-promoting activity for the 17 patients with fulminant hepatic failure was about 16 times higher than that obtained for normal human serum. This growth-promoting activity of the patients' blood was not related to sex, age, clinical outcome of the patients or type of fulminant hepatic failure, but was intimately related to the clinical grade of hepatic coma. Sera or plasma with Grade III and IV coma showed stimulatory activity on DNA synthesis more markedly than sera or plasma from patients with coma of less than Grade II. In the surviving group, this activity decreased as the hepatic coma of patients improved. In fact, this activity of sera from patients at the recovery stage showed no significant increase compared with that of normal human serum. In the group of terminal patients, this activity increased as the coma developed.(ABSTRACT TRUNCATED AT 250 WORDS)

Determination of the integrated CT number of the whole liver in patients with severe hepatitis: as an indicator of the functional reserve of the liver.

A study was conducted to estimate the functional reserve of the liver of patients with severe hepatitis by computed tomography (CT), in particular employing the integrated CT number of the whole liver (ICTN). ICTN was calculated by integrating the product of "area" times "mean CT number" of the liver in each CT slice for the entire height of the liver. The following results were obtained: 1) In patients with fulminant hepatitis (FH) as well as those with subacute hepatitis (SAH), ICTN was found to be significantly lower as compared to that of patients with acute hepatitis (AH) or non-hepatic diseases. In addition, in FH and SAH patients, ICTN showed a larger degree of decrease when compared with such conventional parameters as either estimated liver volume or mean hepatic CT number. Thus, ICTN seems to more sensitively reflect the changes in functional reserve of the liver. 2) ICTN showed significant positive correlations with prothrombin time and plasma BCAA/AAA ratio, and a significant negative correlation with plasma methionine level. 3) Time course of changes in ICTN correlated well with the clinical features of severe hepatitis. In particular, patients with initial ICTN values above 20 l.HU/m2 of body surface area showed significantly higher survival rate than those with initial ICTN below 20. In conclusion, ICTN well indicates the functional reserve of the liver, and is further suggested to be valuable as a parameter to predict the prognosis of patients with severe hepatitis.

[Ultrasonic determination of the common carotid and brachial artery blood flow in patients with acute hepatic failure--with special reference to a decrease in common carotid artery blood flow and its relationship with brain edema].

A study was conducted to elucidate characteristics of circulatory parameters in patients with acute hepatic failure (AHF) employing Swan-Ganz catheter method and, in particular, ultrasonic quantitative flow measurement (QFM) system. The following results were obtained: 1) In five AHF patients who received Swan-Ganz catheter examinations, significant increases of cardiac index as well as decreased systemic vessel resistance were observed. 2) QFM in 11 patients with AHF revealed a significant increase of brachial artery blood flow (Br.F.), whereas common carotid blood flow (Ca.F.) was found to be significantly decreased. Thus, ratio of Ca.F./Br.F. showed a marked reduction as compared with that of control patients. 3) Vessel resistances measured by QFM were found to be significantly reduced in brachial artery, whereas markedly elevated in common carotid artery. 4) Those changes of circulatory parameters as described above were found to restore toward normal in parallel with the improvement of clinical features. 5) Vessel resistances of common carotid artery (Ca.R.) of AHF patients showed a significant negative correlation with CT values in the white matter of the brain, being regarded to well represent the degree of brain edema. In addition, in a case of AHF in whom intracranial pressure (ICP) was directly measured, time course of changes in Ca.F. was found to be in "mirror image" with that of ICP. Thus, it is strongly suggested that the increase of Ca.R. may well be induced, at least in part, by the elevated ICP in AHF patients.