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Biomedical subjects

Samuel S Lee

Publications and source records attributed to Samuel S Lee.

33 records · Page 2Linked to original sources
PubMed2003

Change in lipid profile and impairment of endothelium-dependent relaxation of blood vessels in rats after bile duct ligation.

Hyperlipidemia, a condition normally observed in cholestatic liver disease, is also a risk factor for the development of atherosclerosis. The relationship between the elevation of lipoproteins in cholestatic liver diseases and atherosclerosis formation has not been elucidated. In this study, we propose that the impairment of endothelium-dependent relaxation (EDR) of blood vessels in cholestatic liver diseases may lead to the development of atherosclerosis. Using bile duct ligation (BDL) in rats as a model, we examined the liver function, serum lipid profile, EDR and morphologic change of the aorta from both sham operated and BDL rats. Significant increases in liver and spleen weights, serum alanine transaminase (ALT) and aspartate transaminase (AST) activities and the bilirubin level were observed in BDL rats. Upon bile duct ligation, the total and low-density lipoprotein cholesterol levels were increased but the high-density lipoprotein cholesterol and triglyceride levels were reduced. Less contractility and lowered response to acetylcholine-induced relaxation were found in aorta segments. In addition, the acetylcholine-induced relaxation was blocked by both L-NAME and 15 mM KCl. Our results suggest that both nitric oxide and endothelium-derived hyperpolarizing factor are important elements for the impairment of the EDR in BDL rats. In addition, a mild atrophy of the media of the aorta was detected in BDL rats. We conclude that the alterations of lipid profile and the mild atrophy of the media may lead to the impairment of EDR in the aorta in BDL rats, and these factors may potentiate the development of atherosclerosis.

Acetylcholine↗
PubMed2003

Cardiac hepatopathy: clinical, hemodynamic, and histologic characteristics and correlations.

Cardiac hepatopathy, hepatic injury caused by cardiac dysfunction, is a common entity but has been characterized incompletely, particularly the relationship between hemodynamics and histology. We aimed to describe the clinical, biochemical, hemodynamic, and histologic characteristics of this disorder. Eighty-three patients from 2 tertiary referral centers were studied. Patients were divided into 3 groups based on the duration of cardiac dysfunction: (1) acute (n = 12); (2) chronic (n = 53); and (3) acute on chronic (n = 18). Results showed that serum aminotransferase levels were increased typically, particularly in the acute group (median aspartate aminotransferase level was 30.2 times the upper limit of normal [range, 1-100]; P <.0001 vs. the chronic group). The most salient hemodynamic features were elevated right atrial (14 mm Hg [range, 1-29]), and hepatic venous pressures (wedged: 18 mm Hg [range, 5-35]; free: 15 mm Hg [range, 2-30]). The hepatic venous pressure gradient was normal in most (81%), correlated moderately with the aminotransferase levels (aspartate aminotransferase level: r =.59; P <.0001), and associated with the presence of centrilobular necrosis and inflammation, periportal necrosis, and stainable hepatic iron (P <.05 for all comparisons), but not fibrosis. Sinusoidal dilatation was associated with higher right atrial (P =.047) and free hepatic venous pressures (P =.06). Although cirrhosis was rare (n = 1), centrilobular fibrosis was common (74%) and not associated with any hemodynamic measurement. In conclusion, cardiac hepatopathy has diverse clinical, hemodynamic, and histologic manifestations that vary with the temporal course of cardiac dysfunction. Hepatic fibrosis is common, but does not correlate with systemic or hepatic hemodynamics.

Adolescent↗
PubMed2002

The role of selectins and integrins in adenovirus vector-induced neutrophil recruitment to the liver.

Adenovirus vectors for human gene therapy induce early host inflammatory responses in transduced tissues that limit gene transfer efficiency and can result in significant morbidity. The present study aimed to elucidate the cellular mechanisms underlying the acute inflammation induced by adenovirus vectors in the liver. Leukocyte rolling and adhesion in response to an intravenously administered adenovirus vector was examined by intravital microscopy in mouse liver. Adenovirus vectors significantly increased leukocyte rolling and adhesion in the postsinusoidal venules within minutes of transduction. Unlike other inflammatory states in the liver, no leukocyte retention was seen in the sinusoids in response to adenovirus vector administration. Inhibition of P-selectin, alpha(4)-integrin, and E-selectin was necessary to completely block leukocyte rolling and subsequent adhesion. The administration of an anti-alpha(4)-integrin antibody alone significantly reduced leukocyte adhesion. In contrast, adenovirus vector-induced leukocyte adhesion was unchanged in CD18-knockout mice. Depletion of circulating neutrophils eliminated leukocyte rolling and adhesion in response to adenovirus vector transduction in the liver. In conclusion, adenovirus vectors induce rapid neutrophil-mediated inflammation in the post-sinusoidal venules by selectins and alpha(4)-integrin but surprisingly not by CD18.

Adenoviridae↗
PubMed2002

Prognostic factors and early predictability of sustained viral response with peginterferon alfa-2a (40KD).

BACKGROUND/AIMS: Baseline factors and early decline in serum hepatitis C virus RNA are predictive of sustained virological response to interferon therapy in patients with chronic hepatitis C. We evaluated the prognostic value of baseline factors and early viral RNA among patients treated with peginterferon alfa-2a (40KD). METHODS: Data were pooled from three randomized trials involving 814 patients treated with peginterferon alfa-2a (40KD) (90, 135, or 180 mirog). Stepwise and multiple logistic regression identified independent baseline factors associated with response. Receiver operating characteristic curves for both absolute values and log(10) decline in viral RNA at 4, 8, 12 and 24 weeks of therapy were created. RESULTS: Independent prognostic factors for sustained virological response included viral genotype non-1, low pretreatment viral load, age (<40 years), no cirrhosis and body weight (<85 kg). In addition, alanine aminotransferase quotient (>3) and histological activity index score (>10) were also independently prognostic. Receiver operating characteristic curves showed that detectable or less than 2-log(10) decline in viral RNA at week 12 predicted sustained virological non-response (negative predictive value is 98%) . CONCLUSIONS: In patients with chronic hepatitis C treated with peginterferon alfa-2a (40KD), the decision to continue or stop treatment can be made as early as week 12.

Adult↗
PubMed2002

Hyperdynamic circulation in portal-hypertensive rats is dependent on central c-fos gene expression.

Portal hypertension is associated with hyperdynamic circulation, but the pathogenesis remains unclear. To clarify the role of central cardiovascular regulatory mechanisms, several protocols were conducted in rats with portal hypertension due to portal vein stenosis (PVS). Neuronal activation was quantified by immunohistochemical staining for Fos, the protein product of the c-fos gene. Fos expression in several brain nuclei with cardiovascular-regulatory roles was examined at 1, 3, 5, and 10 days following PVS surgery. This was correlated with development of cardiovascular changes measured at the same time points. Finally, Fos expression in the nucleus tractus solitarius (NTS) was blocked by local microinjection of c-fos antisense oligonucleotides twice daily for 5 days following PVS. The results showed that Fos-positive neurons were significantly increased in the paraventricular nucleus of hypothalamus, supraoptic nucleus, ventrolateral medulla, and NTS, detectable at day 1 and persistently increased at every day examined in the PVS rats. However, the hyperdynamic circulation developed between days 3 to 5. Administration of c-fos antisense oligonucleotides eliminated the hyperdynamic circulation in PVS rats, but had no effect on sham-operated controls. We conclude that the activation of central cardiovascular-regulatory nuclei, through a c-fos-dependent pathway, is necessary for development of hyperdynamic circulation in portal-hypertensive rats.

Animals↗
PubMed2002

Evolution of autoimmune hepatitis to primary sclerosing cholangitis: A sequential syndrome.

Recently, the autoimmune hepatitis (AIH)/primary sclerosing cholangitis (PSC) overlap syndrome has been reported increasingly. In this syndrome, patients present with features of both AIH and PSC. It has been suggested that the 2 diseases may be sequential in their occurrence, whereby patients have features of AIH and then after a number of years develop features of PSC, but clear confirmation of evolution has not been documented in adults. We describe 6 adult cases in which PSC was diagnosed many years after well-established AIH. Six patients are described in whom AIH definitely was diagnosed at presentation. No evidence of biliary disease was noted on the initial liver biopsy or endoscopic retrograde cholangiography (ERCP). All patients responded well to immunosuppressive therapy. After an average duration of follow-up of 4.6 years they became resistant to immunosuppression, and developed clear features of PSC, which was confirmed by ERCP in all patients. The average age of the patients at first presentation was 31.3 years, 2 were women and 4 were men, and 3 had ulcerative colitis. We found no specific features at presentation that could predict this evolutionary outcome. In conclusion, patients with well-established AIH can, after variable duration of follow-up, develop PSC. In patients with AIH who become resistant to immunosuppression or develop significant cholestasis, PSC should be ruled out by ERCP.

Adolescent↗
PubMed2002

Role of ICAM-1 in chronic hepatic allograft rejection in the rat.

The pathogenesis of hepatic allograft rejection remains unclear. We aimed to clarify the early role of intercellular adhesion molecule-1 (ICAM-1)-mediated cell recruitment in chronic hepatic rejection. Liver transplantation was performed from Lewis to Lewis rats (isograft controls) and from Lewis to Brown Norway rats (allograft rejection group). The allografted rats were treated with either ICAM-1 antisense oligonucleotides (10 mg. kg(-1). day(-1) x 6 days ip) or a control preparation (either ICAM-1 missense oligonucleotide or normal saline). Hepatic leukocyte recruitment in vivo was studied on day 6 by using intravital microscopy. Liver histology, biochemistry, and survival rates were also examined. Leukocyte adhesion in terminal hepatic venules was significantly increased in the rejection group compared with isograft controls. Antisense ICAM-1 in the allografted group effectively reduced leukocyte adhesion. Histology and liver chemistry were less deranged in the antisense-treated groups compared with control-treated allografted rats. In the allograft groups, survival was significantly prolonged in the antisense-treated rats (42.3 +/- 1.2 days) compared with the controls (25.2 +/- 2.7 days). These results showed that early leukocyte recruitment in the hepatic microvasculature of rejecting allografts is ICAM-1 dependent and suggest that impacting on early cell recruitment can significantly ameliorate chronic rejection.

Animals↗
PubMed2002

Nitric oxide and renal and cardiac dysfunction in cirrhosis.

Nitric oxide (NO) has diverse physiological and pathophysiological effects. The roles of NO in the renal and cardiac dysfunction found in cirrhosis are reviewed. In the kidneys of experimental animals with cirrhosis, several lines of evidence speak in favour of an enhanced production of NO, through the activation of both endothelial constitutive and inducible isoforms of NO synthase. In contrast with the situation in normal animals, inhibition of NO synthesis in rats with cirrhosis improves sodium and water excretion via blood pressure-dependent and -independent mechanisms, which indicates that the renal sodium and water retention of cirrhosis is related to an excess of NO production. The deleterious effect of excessive NO on the kidney may be mediated by peroxynitrite, a potent oxidant that is readily formed whenever superoxide anions and the *NO radical are produced together. The peroxidation of arachidonic acid by peroxynitrite leads to the formation of F(2a)-isoprostanes, which are powerful renal vasoconstrictors. F(2a)-isoprostane levels are correlated with the severity of liver injury during cirrhosis. However, whether peroxynitrite or F(2a)-isoprostanes are the elusive mediator of the NO-induced renal alterations in cirrhosis remains to be firmly established. NO is also involved in cardiac contractility, probably in the normal heart as well as in disease conditions such as non-cirrhotic and cirrhotic cardiomyopathy. In the latter state, evidence suggests that inducible NO synthase attenuates ventricular contractility, mediated by cGMP. Another gas that transduces its signal through cGMP, carbon monoxide, is also likely to play a role in cirrhotic cardiomyopathy, but the nature of the interaction between NO and carbon monoxide in this syndrome remains unclear.

Animals↗
PubMedDate not supplied

Health and socioeconomic status differences among antibody hepatitis C positive and negative transfusion recipients, 1986-1990.

OBJECTIVE: To characterize the socioeconomic and health status, disease symptoms of anti-HCV-positive and negative transfusion recipients. METHODS: A cross-sectional interviewer-administered survey of subjects identified through the British Columbia Blood Recipient Program. Study subjects were 18 years and over and had to have had a transfusion between August 1, 1986 and June 30, 1990 and completed an interview of satisfactory quality. Anti-HCV-positive subjects were those seeking monetary compensation from the provincial and Canadian governments and the comparison group was randomly selected from a pool of anti-HCV-negative subjects. The study was designed to detect an assumed difference of 20% in signs and symptoms between the two groups. Statistical comparisons were conducted using bivariate and multivariate logistic regression analyses. RESULTS: A total of 241 and 222 anti-HCV-positive and negative subjects were respectively interviewed and met the study's eligibility criteria. Results from the multivariate analysis indicated that anti-HCV-positive recipients were more likely to have two or more clinical symptoms (OR = 3.53; 95% CI: 1.44, 8.70), to be in worse health status as compared to ten years previous (OR = 1.60; 95% CI: 1.30, 1.96), to have a higher illness intrusiveness rating (OR = 1.35; 95% CI: 1.25, 1.46), and to be younger (OR = 0.97; 95% CI: 0.95, 0.98). CONCLUSION: Our results show that persons exposed to HCV were more likely to have had two or more clinical symptoms, be male, have worse health status as compared to ten years previous, have a higher illness intrusiveness rating, and be younger in age.

Aged↗
PubMedDate not supplied

Cirrhotic cardiomyopathy.

Liver cirrhosis is associated with a wide range of cardiovascular abnormalities. These abnormalities include hyperdynamic circulation characterized by an increase in cardiac output and a decrease in peripheral vascular resistance. Despite the increased cardiac output, impaired ventricular contractility in response to both physiological and pharmacological stimuli has been described. Other cardiac abnormalities include structural changes including enlargement or hypertrophy of different cardiac chambers and electrophysiological changes such as QT prolongation. This constellation of cardiac abnormalities is termed cirrhotic cardiomyopathy. The pathogenic mechanisms of cirrhotic cardiomyopathy are multifactorial and include cardiomyocyte plasma membrane physico-chemical changes, attenuated stimulatory pathways, and enhanced activity of inhibitory systems. Accumulating evidence suggests that cirrhotic cardiomyopathy plays a major role in the pathogenesis of cardiac dysfunction following liver transplantation or transjugular intrahepatic portosystemic shunt placement. Recent research also strongly suggests that cirrhotic cardiomyopathy contributes to the pathogenesis of hepatorenal syndrome, especially following infections such as spontaneous bacterial peritonitis. Treatment of this syndrome remains largely empirical. Successful liver transplantation is thought to improve all the organ-related hemodynamic dysfunctions, including hepatopulmonary syndrome, cerebral hypoperfusion, hepatorenal syndrome, and cirrhotic cardiomyopathy. The prolonged QT interval normalizes following liver transplantation. Thus, liver transplantation appears to be the ultimate treatment for the cardiovascular complications of cirrhosis.

Biomarkers↗