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Severe acute liver injury due to accidental or intentional acetaminophen overdose presents a major clinical dilemma often requiring liver transplantation. In the present study, liver regeneration after profound liver injury in mice challenged with acetaminophen was facilitated by the exogenous addition of ELR-containing CXC chemokines such as macrophage inflammatory protein-2 (MIP-2), epithelial neutrophil-activating protein-78 (ENA-78), or interleukin 8. Intravenous administration of ELR-CXC chemokines or N-acetyl-cysteine (NAC) immediately after acetaminophen challenge in mice significantly reduced histological and biochemical markers of hepatic injury. However, when the intervention was delayed until 10 h after acetaminophen challenge, only ELR-CXC chemokines significantly reduced liver injury and mouse mortality. The delayed addition of ELR-CXC chemokines to cultured hepatocytes maintained the proliferation of these cells in a CXCR2-dependent fashion after acetaminophen challenge whereas delayed NAC treatment did not. These observations demonstrate that ELR-CXC chemokines represent novel hepatic regenerative factors that exhibit prolonged therapeutic effects after acetaminophen-induced hepatotoxicity.

Cytokines play an important role in the pathogenesis of many diseases including liver failure. Both newly described and 'classic' pro-inflammatory cytokines, such as tumour necrosis factor-alpha, have been implicated in both hepatic injury and liver regeneration. In addition, increased circulating concentrations of these cytokines suggest they may have a hormone-like endocrine effect on tissues distant to their production, leading to the hypotension, lung injury and cerebral oedema that occur in such patients. Increased understanding of the cytokine networks involved in acute liver failure may lead to the development of novel therapies, which may reduce the requirement for liver transplantation in this condition.

Little information exists about the efficacy of various brace designs to restrict inversion during lateral movements. The purpose of the study was to determine whether semi-rigid stirrup (AirCast Sport Stirrup), semi-rigid modified stirrup (Malleoloc), or a soft, sleeve design (Swede-O) brace varied in their abilities to restrict inversion without hindering plantar/dorsiflexion when a lateral cutting movement is performed compared to a no-brace condition (No-Br). Nineteen volunteers who had previously sprained their right ankles performed 10 sideward cutting trials/brace condition. Based on kinematic data, captured using high-speed cameras, none of the braces restricted inversion compared to the No-Br condition. Plantar flexion was inhibited for all braces, and less dorsiflexion was exhibited for the Swede-O. For three participants, greater toe-in landings were observed for the Swede-O. Based on chi-square analyses, the participants rank of braces for stability and overall performance in decreasing order: Malleoloc, AirCast, Swede-O. It was concluded that the participants may have exhibited injury avoidance behavior during conditions perceived to be less stable, thereby reducing inversion when wearing no brace or the Swede-O brace. It also is tenable that the motion of the shoe was influenced by the presence of the braces, hence, no inversion restriction was observed.

Objective: The purpose of this study was to determine how foot landing position influenced the ground reaction forces of two coordinate systems during gait., Design: Values of ground reaction forces components as expressed in two coordinate systems (room, foot) were used to compare ground reaction forces of different foot landing position., Background: Non-neutral foot landing position during gait could influence the mechanics of the whole body motion and/or the foot-ankle complex and produce different ground reaction forces patterns compared to a neutral foot landing position., Methods: Thirty females were assigned to a foot landing group: toe-out, toe-in or neutral. Each participant walked 10 trials across a force platform while three-dimensional motion was captured., Results: No differences were observed for vertical or anteroposterior ground reaction forces variables between groups for either coordinate system. For medio-lateral forces of both coordinate systems, toe-out participants exhibited greater first lateral and second medial maximum forces and exhibited greater impulses., Conclusion: For toe-out participants, greater medio-lateral ground reaction forces of the room coordinate system indicate excessive forces are generated by toe-out participants that do not contribute to moving the participant forward. Furthermore, medio-lateral loading on the foot increases proportionally with the degree of toe-out., Relevance: Establishing norms for clinical populations requires understanding of factors that can influence ground reaction force (GRF). Foot landing position (FLP) only affects the medio-lateral forces. Excessive toe-out landing has been surmised to be related to injury. Greater forces acting medio-laterally to the foot's long axis may have a relevant effect on in/eversion loading of the foot.

Whey acidic proteins (WAP) from the mouse, rat, rabbit, camel, and pig comprise two "four-disulfide core" domains. From a detailed analysis of all sequences containing this domain, we propose a new PROSITE motif ([KRHGVLN]-X-¿PF¿-X-[CF]-[PQSVLI]-X(9,19)-C-¿P¿-X-[DN]-X-¿N¿ -[CE]-X(5)-C-C) to accurately identify new four-disulfide core proteins. A consensus model for the WAP proteins is proposed, based on the human mucous proteinase inhibitor crystal structure. This article presents a detailed atomic model for the two-domain porcine WAP sequence by comparative modeling. Surface electrostatic potential calculations indicate that the second domain of the pig WAP model is similar to the functional human mucous proteinase inhibitor domains, whereas the first domain may be nonfunctional.

Profound hepatocellular injury is often a consequence of adenovirus-mediated gene therapy or acetaminophen ingestion. The aim of the present study was to examine the role of a CXC chemokine, macrophage inflammatory protein-2 (MIP-2), in the hepatotoxic response by mice infected with adenovirus and challenged with acetaminophen. CD1 mice that received a replication-defective human type 5 adenovirus vector (Ad70-3) intravenously exhibited hepatic injury that peaked at 24 h after infection. In contrast, mice that received a similar adenovirus vector containing a rodent MIP-2 cDNA insert had no hepatic injury at any time after infection. The combination of Ad70-3 infection and an intraperitoneal challenge with 400 mg/kg of acetaminophen was fatal in 50% of the mice, but only 10% of the AdMIP-2 group receiving acetaminophen were similarly affected. Furthermore, AdMIP-2 mice had significantly lower hepatic injury and serum aminotransaminases compared with the Ad70-3 group. However, AdMIP-2 infection in mice lacking the CXC chemokine receptor that binds MIP-2, CXCR2, did not attenuate any of the markers of liver injury after adenovirus and acetaminophen challenge. AdMIP-2 treatment of CD1 mice was also associated with significantly decreased leukocyte infiltration into the liver and an earlier increase in hepatic 3H-thymidine incorporation compared with the control group. Taken together, these data demonstrate that MIP-2 has a protective role in both adenovirus- and acetaminophen-mediated hepatotoxicity, and suggest that MIP-2 may promote rapid hepatic regeneration following acute hepatic injury.

The Scottish Liver Transplant Unit is now in its sixth year of existence. We present the outcome of the first 165 transplants which have at least 12 months follow up. The overall patient (n = 143) survival rates at 1, 3 and 5 years were 86.6%, 79.3% and 74.7% and the graft survival rates were 76.9%, 69.1% and 64.8%. The one year survival rate for patients with chronic liver disease (n = 113) was 89.2% compared with 76.6% for acute liver failure (Breslow = 0.05). The one year survival rate for the first 71 patients receiving their primary graft was 81.7% compared with 91.5% for the subsequent 71 patients (Breslow = 0.09). The majority of deaths (n = 29) were due to sepsis (n = 7), at operation (n = 6) or due to graft vascular insufficiency (n = 4). There were two cases of de novo haematological malignancy. The outcome of the first 165 transplants in Scotland compares very well with other countries throughout the world.

The social use of ecstasy (methylenedioxymethampheta-mine, MDMA) and amphetamines is widespread in the UK and Europe, and they are popularly considered as 'safe'. However, deaths have occurred and hepatotoxicity has featured in many cases of intoxication with amphetamine or its methylenedioxy analogues such as ecstasy. Recreational use of these drugs presents an important but often concealed cause of hepatitis or acute liver failure, particularly in young people. The patterns of liver damage and multiple putative mechanisms of injury are discussed. Recognition of the aetiological agent requires a high index of suspicion. Optimum management of the resultant liver damage, including the controversial role of liver transplantation for fulminant hepatic failure, is also discussed.

One of the major constraints to transplantation of solid organs is lack of availability of grafts and any attempt to use all available donors is to be welcomed. We address the possibility of expanding the transplant donor pool by inclusion of more patients who have suffered intoxication with drugs premortem. Particularly important in this context is the exclusion of organ-specific damage, and also infective risk to the potential recipient due to viral causes in the donor.

Background: The clinical significance of a single assessment of circulating hepatitis C virus (HCV) RNA and its relation to the level of intrahepatic HCV RNA remains unclear., Aims: To investigate the relation between intrahepatic HCV levels and clinicopathological characteristics of chronic HCV infection., Patients: Ninety eight consecutive patients with chronic HCV infection were studied; none had received alpha interferon therapy. Of these, 12 patients were repeatedly negative for HCV RNA in serum by reverse transcriptase polymerase chain reaction (RT-PCR)., Methods: After diagnostic laparoscopy and liver biopsy, semiquantitative analysis of intrahepatic HCV RNA levels was carried out by limiting dilution of HCV cDNA. HCV genotypes were assessed in 96 patients by restriction fragment length polymorphism analysis of HCV cDNA., Results: Ten out of 12 patients who were RT-PCR negative for HCV RNA in serum were RT-PCR positive in liver; however, this group had a significantly lower intrahepatic HCV level and serum aminotransferase level than the remaining 86 patients. Histological severity (cirrhosis: n = 10); histological activity index; HCV genotype (genotype 1: n = 41; genotype 2: n = 12; genotype 3: n = 36; genotype 4: n = 7); mode of infection (intravenous drug abuse: n = 58; post-transfusion: n = 10; haemophiliac: n = 4; sporadic: n = 26) and alcohol abuse did not affect the intrahepatic virus level. There was no correlation between patient age, duration of infection, and intrahepatic HCV level., Conclusions: Intrahepatic virus levels were not determined by host factors (age of patient, mode or duration of infection) or by virus factors (HCV genotype). Repeatedly negative RT-PCR for HCV RNA in serum does not indicate absence of HCV from the liver.

A 17.5 kDa protein was isolated from porcine whey by reverse phase HPLC and identified as a putative whey acidic protein (WAP) homologue by sequencing 35 and 40 amino acid residues of the amino- and carboxy-terminus respectively. Degenerate oligonucleotides to both of these amino acid sequences were designed and used in reverse transcriptase PCR with RNA from lactating porcine mammary gland as a template. A 162 bp PCR fragment was detected and sequenced. Compilation of the deduced and determined amino acid sequence revealed a protein of 111 amino acids, which had approximately 75, 50, 40 and 35% similarity at amino acid level to camel, rabbit, rat and mouse WAP respectively. It also included the four-disulphide core characteristic of all WAP proteins and most Kunitz-type protease inhibitors. This provides the first unequivocal evidence for WAP secretion in the pig. SDS PAGE analysis of the whey fraction showed that WAP is secreted as a major protein in sow's milk from farrowing to weaning. The molecular mass of WAP in SDS PAGE was significantly greater than the 11.7 kDa determined from amino acid sequence, indicating that porcine WAP is possibly glycosylated. Northern analysis detected a single mRNA transcript of approximately 600 bp in porcine RNA from the mammary gland of lactating sows. To examine the hormone-regulated expression of the WAP gene the mammary glands of sows at day 90 of pregnancy were biopsied and explants cultured for 3 days in the presence of various combinations of porcine insulin (I), cortisol (F) and porcine prolactin (P). Northern analysis of RNA extracted from the tissue indicated that WAP gene expression was barely detectable in the mammary gland prior to culture and there was no increment in explants cultured in the presence of I and F. However, a significant increase in the accumulation of WAP mRNA was observed in explants cultured in I, F and P. A similar result was observed for beta-casein and alpha-lactalbumin gene expression.

Little is known about shear loading patterns during dance movements. The purpose of the study was to investigate the effect of jumping distance (JD) on contributors of ankle and knee shear forces (SF) generated during the landing phase of traveling jumps. Six female dancers performed 10 trials each at 30, 60, and 90% maximum jump distance (JD) and 15 jumps ranging from 35 to 100% JD. A sagittal view of the right leg landing onto a force platform was filmed using a high-speed cine camera. Greater ankle and knee joint reaction shear forces (JRSF) and quadriceps SF (QuadSF) were observed (P < 0.05) at increased JD. Although the triceps surae SF (TriSurSF) also increased at greater JD for all but one participant, the effect on minimizing the increase in the ankle SF was minor. The peak QuadSF magnitude and rate of loading were always greater than the corresponding knee JRSF variables. However, the increased QuadSF that occurred at longer jumps led to increased knee SF for only half of the participants.

Knowledge of the magnitude and rate of applying axial forces (AF) during actual dance movements is necessary for understanding the etiology of chronic injuries and osteoarthritis. The purpose of this study was to investigate the effect of jumping distance on component ankle and knee joint AFs generated during the landing phase of traveling jumps. Six female dancers performed 10 jumps each at 30, 60, and 90% maximum jump distance (JD) and 15 jumps ranging from 35 to 100% JD. A sagittal view of the right leg landing onto a force platform was filmed. Greater ground reaction force maxima, knee flexion, knee and ankle flexion velocity, tibial landing angle, net ankle and knee joint moment maxima, ankle and knee joint reaction AFs, and quadriceps AFs (QuadAF) peak magnitudes and rates of AF application (dFmax/dt) were observed (P < 0.05) at increased JD. The QuadAF was a more important determinant of knee AF than joint reaction AF. Increased quadriceps force was useful for accommodating impact forces but served to increase its contribution to Knee AF, particularly during the later portion of the impact phase. High impact situations create significant magnitudes (e.g., 14 BW) and dFmax/dt of muscle AFs which could contribute to excessive joint wear.

In a significant number of cases of fulminant (presumed viral) hepatitis worldwide, no aetiological agent has been identified. Recently, it has been suggested that a newly described flavivirus, GBV-C, is responsible for some of these cases. This study aimed to assess the clinical significance of GBV-C RNA, demonstrated by reverse transcriptase-polymerase chain reaction (RT-PCR), in the serum of patients with fulminant non-A to E hepatitis. Twenty-three consecutive cases of non-A to E fulminant hepatitis were included in the study. GBV-C RNA was reverse transcribed and amplified using two RT-PCR based detection methods. Medical records were examined to assess clinical history, duration and mode of infection, transfusion history, liver histology and clinical outcome. Five (three female, two male; mean age 21.2 years) of 23 patients had GBV-C RNA detected in their serum by RT-PCR: all five patients were RT-PCR positive following amplification by primers specific for the 5' non-coding region (NCR), whilst four were positive by primers for the NS3 region. Prior to the onset of illness, two patients had risk factors for transmission of an infectious agent; however, all five patients had been transfused during their illness, prior to testing for GBV-C. Of these, two (of two in whom serum was available) were negative for GBV-C after the onset of fulminant hepatitis but before their first transfusion. This study does not support the hypothesis that the detection of hepatitis G virus (HGV)/GBV-C RNA in the serum of patients with fulminant hepatitis indicates a causal association. However, it does demonstrate that a careful transfusion history and screening of blood products is vital before the importance of GBV-C in the aetiology of fulminant hepatitis can be established.

Background: Laparoscopic liver biopsy can be safely performed using local anesthesia and intravenous sedation, but the frequency of hypoxemia is unknown., Methods: We prospectively studied 68 patients undergoing diagnostic laparoscopy and liver biopsy managed by a standard protocol., Results: The mean duration of laparoscopy was 27 +/- 5.53 minutes; the mean dose of diamorphine administered was 6.9 +/- 2.7 mg; diazepam, 7.05 +/- 3.52 mg. The baseline arterial oxygen saturation was 95.6% +/- 2.5% and trough was 85% +/- 5.1%. A fall of greater than 4% saturation from the baseline occurred in 64 out of 68 patients (94%). The mean decrease in saturation was 10.1% +/- 5.4%. An arterial oxygen saturation of less than 85% was seen in 32 patients (47%). There was no correlation between the fall in oxygen saturation and the dose of diamorphine or diazepam, the duration of procedure, body mass index, hemoglobin, or volume of pneumoperitoneum induced. One-way analysis of the variance failed to show a significant relationship between the degree of oxygen saturation and Child's class, etiology of liver disease, or smoking habit., Conclusions: In this study, we demonstrated that significant desaturation is common in diagnostic laparoscopy with liver biopsy and is likely due to a combination of different pharmacologic and physiologic effects. We recommend continuous monitoring of both arterial oxygen saturation and supplemental oxygen for all patients throughout laparoscopy.

A description of the hardware and software used to create movement patterns that differ spatially and temporally is explained. These tasks are presented to participants using a virtual pattern generator.

Chronic alcohol misuse is the most common cause of hepatic steatosis. The accumulation of lipid is reversible with abstinence, but some workers have suggested that the severity of hepatic steatosis predicts the progression with time to alcoholic cirrhosis. Triacylglycerol is the major accumulating lipid and subcellular fractionation and electron microscopy studies have shown accumulation of lipid droplets within the golgi fraction. This is consistent with the reports in both experimental animals and man of reduced hepatic secretion of very low density lipoprotein triacylglycerol which may be secondary to acetaldehyde-induced disruption of the cytoskeletal elements. In addition, hepatic production of triacylglycerol increases, but most studies in animal models suggest that increased triacylglycerol synthesis becomes less important as hepatic lipid accumulates.

The clinical history and examination is essential in the evaluation of patients with liver disease. This chapter details important points in the clinical history and examination allowing the physician to identify likely causes of liver damage and their investigation. The evaluation should allow the physician to differentiate acute and chronic liver diseases, and in the latter case separate those with obstructive or chronic parenchymal liver disease. It should also allow identification of important complications such as encephalopathy, ascites and portal hypertension. Identification of these main features or complications of liver disease by the clinical evaluation leads to a logical plan of investigation and prompt diagnosis and management of the liver disease.

Objectives: Transjugular intrahepatic portosystemic stent-shunts (TIPSS) have been shown to reduce portal hypertension consistently and have recently been reported to arrest active variceal hemorrhage. This retrospective and nonrandomized study compares the results of TIPSS with esophageal transection (ET) and devascularization in patients with uncontrolled variceal hemorrhage admitted to a single center with an interest in variceal bleeding., Patients and Methods: Two hundred and sixty cirrhotic patients have been referred with variceal bleeding over the past 7 yr. In 41 patients (15.8%), hemorrhage was uncontrolled despite two treatments with sclerotherapy. Thirty-eight patients were eligible for analysis. Nineteen were considered for ET and 19 for TIPSS. Patients in the two groups were well matched for age, sex, etiology of liver disease, and its severity and complications. They have been followed for 13 patient years (TIPSS-7, longest 20 months; ET-6, longest 23 months). Data for survival and rebleeding were analyzed by the Kaplan-Meier method on an intention-to-treat basis., Results: Seven of the 19 were considered unfit for surgery, and 12 underwent esophageal transection and devascularization. TIPSS was undertaken successfully in 17 patients, the Palmaz stent being used in 4 and the Wallstent in 13. Successful TIPSS reduced the mean portal pressure gradient from 22.2 (SE 1.2) to 9.7 (SE 0.7) mm Hg (p < 0.001). Mortality within 30 days of the initial bleed was 42% in the TIPSS group compared with 79% in the ET group (p < 0.05). Rebleeding occurred in 15.6% patients with TIPSS, compared with 26.2% in the ET group. Encephalopathy in the two groups of patients was not significantly different (TIPSS 25% and ET 22%). TIPSS was followed by active infection in 20% compared with 36% after ET., Conclusions: This study shows that the overall mortality in this group of patients is high whatever the type of treatment used. TIPSS can be performed successfully on these patients who are often not suitable for surgery. Mortality rates were significantly lower in patients treated by TIPSS. Compared with ET, TIPSS should be regarded as the preferred mode of treatment for uncontrolled variceal hemorrhage in patients with cirrhosis.

Objective: To test the hypothesis that elevated serum levels of intercellular adhesion molecule-1 (sICAM-1), vascular cell adhesion molecule-1 (sVCAM-1), (s)E-selectin, (s)P-selectin and soluble interleukin-2 receptor (sIL-2R) occur in patients with biochemically inactive autoimmune hepatitis (AICH) compared with controls. Such a finding would suggest continued immune activation, which in the long-term would contribute to the development of cirrhosis in such patients., Methods: sICAM-1, sVCAM-1, sE-selectin, sP-selectin and sIL-2R were measured in serum from 50 patients with AICH, divided into two groups according to whether their serum alanine aminotransferase (ALT) levels were normal (below 40 IU/l) or increased (above 40 IU/l). Fourteen healthy subjects served as controls. Eight patients were followed after the induction of remission with increased immunosuppressive therapy., Results: Elevated levels of sICAM-1, sVCAM-1 and sE-selectin were found in patients with AICH compared with controls, independent of their ALT concentration. Only sICAM-1 was significantly elevated in the patients with active disease compared with patients with inactive disease. sIL-2R concentrations were significantly higher in patients with active disease (ALT above 40 IU/l) compared with controls. sP-selectin concentrations were similar in controls and patients with AICH. In patients with clinical and biochemical relapse, increased steroid therapy was followed by a significant reduction in sICAM-1, sVCAM-1 and sIL-2R. The response of sE-selectin was more variable. sICAM-1 remained elevated in five of the eight patients treated with increased steroid therapy despite normalization of their transaminase levels, sIL-2R, sE-selectin and sVCAM-1 levels. In 52% of patients with biochemically inactive AICH (ALT below 40 IU/l), sICAM-1 was above the control range., Conclusions: These data suggest that patients with AICH have ongoing immune activation despite biochemically inactive disease. This may result in low grade hepatic inflammation and may explain the progression to cirrhosis in patients with AICH despite immunosuppressive therapy.

A micromethod was developed to assay the hepatic activity and subcellular distribution of phosphatidate phosphohydrolase (PAH, EC 3.1.3.4), an important regulatory enzyme in triacylglycerol synthesis, in human needle biopsy specimens. In normal liver PAH is predominantly cytosolic in distribution, but on treatment with oleic acid it shifts to the membranous compartments of the cell, its physiologically active site. The hepatic specific activity of PAH was similar in controls and patients with fatty liver but significantly more of the enzyme was associated with the membranous compartments in patients with severe alcoholic fatty liver. These observations may explain the enhanced rates of triacylglycerol synthesis observed in these patients and may be implicated in the pathogenesis of alcoholic fatty liver.

Oral isosorbide-5-mononitrate (Is-5-Mn) was given in doses of 10 and 40 mg acutely and chronically (twice daily for four weeks), allowing a nitrate free interval to 25 patients with cirrhosis. Both 10 mg and 40 mg Is-5-Mn reduced the hepatic venous pressure gradient acutely and chronically, without evidence of tolerance. This was achieved by a reduction in the wedged hepatic venous pressure. The effect on mean azygos blood flow was variable with no significant mean change seen acutely or after chronic use with either dose. The variability was dependent not on the dose used but on the initial azygos flow; the flow in patients with initially low values increased and those with high azygos flows decreased after nitrate challenge. The development of the porto-collateral flow seems an important parameter in predicting haemodynamic response to Is-5-Mn.

The activity and subcellular distribution, before and after translocation with oleic acid, of hepatic phosphatidate phosphohydrolase (PAH: E.C.3.1.3.4) was measured following acute and chronic administration of ethanol with either 18% or 4.4% total calories as fat, to male Wistar rats. Acute injection produced a significant increase in PAH activity, without affecting the subcellular distribution or translocation of activity from the cytosol into the membraneous compartments induced by oleic acid. PAH activity, subcellular distribution and the translocation of activity by oleic acid was similar in all groups following chronic liquid feeding. Chronic ethanol feeding was associated with significantly increased plasma corticosterone in the ethanol-fed rats compared with controls, independent of the fat content of the diet. Plasma insulin was similar in chronic alcohol fed rats and controls. This suggests that enhanced PAH activity may contribute to triacylglycerol accumulation following acute alcohol injection, but activity normalises as hepatic lipid accumulation progresses and this effect is not due to attenuation of the hormonal effects of ethanol.

Variceal haemorrhage is a common and frequently fatal presentation of cirrhosis. There have been several recent developments in endoscopic therapy, pharmacological therapy and portal shunting, offering new therapeutic options. These are reviewed and followed by a management strategy incorporating these developments with established therapies.

1. Chronic alcohol feeding with a low-fat diet (4.4% total calories) produced a two- to three-fold increase in hepatic triacylglycerol and esterified cholesterol compared with pair-fed low-fat diet controls. Plasma lipids were similar in both groups. 2. Hepatic fatty acid synthesis rates measured in vivo with 3H2O were significantly lower in the alcohol-fed animals than in controls. Activities of hepatic fatty acid synthase (EC 2.3.1.85) and acetyl-CoA carboxylase (EC 6.4.1.2) were reduced in the alcohol-fed rats. 3. These results indicate that enhanced hepatic fatty acid synthesis does not occur in rats fed alcohol and a low-fat diet for 4 weeks, and is thus not implicated in the pathogenesis of alcohol-induced fatty liver.

We assessed the long-term efficacy of transjugular intrahepatic portasystemic stent-shunt (TIPSS) in 64 patients. Insertion was successful in 56 patients (87.5%). The reasons for its use were: variceal bleeding (49); ascites (6); portal hypertensive gastropathy (6); hypersplenism (2); and embolization of a spontaneous shunt (1). Fourteen patients were Childs A, 20 Childs B and 28 Childs C cirrhotics. Two patients were non-cirrhotic; one with amyloidosis and one with non-cirrhotic portal fibrosis. Patients were followed clinically and radiologically (Doppler ultrasonography and routine portography at 6 months). During 33 patient-years of follow-up, 22 died, 12 during index admission (two were procedure-related) and nine were transplanted. Twenty-five patients are alive, with a mean survival of 7.1 (SD 7) months. Variceal rebleeding occurred in 10 patients (22.7%), one of whom died, and was always associated with shunt insufficiency (shunt thrombosis 2, hepatic vein stenosis (HVS) 1, intimal hyperplasia (IH) 4, dislocated stent 1, inadequate stent 2). Clinical encephalopathy was induced in seven patients (17.1%) following TIPSS. All responded to medical therapy, but two required reduction in shunt size. Ascites improved after TIPSS in 36 patients (87.8%), but reaccumulated in seven (17.5%), associated with shunt dysfunction in five (SBP 2, IH 3, HVS 2). Fatal sepsis occurred in two patients, and 14 other episodes of infection required antibiotics. TIPSS is a useful treatment for variceal bleeding, resistant ascites and portal hypertensive gastropathy. Shunt dysfunction and sepsis occur frequently, and regular surveillance is necessary.

Two unique methodological strategies were used to investigate the influence of retroactive inhibition on recall within a contextual interference paradigm. Three independent blocked groups, blocked without retroactive inhibition (BL-without), blocked with 18 trials of retroactive inhibition (BL-18), and blocked with 36 trials of retroactive inhibition (BL-36), were created that varied in order of presentation of tasks. By testing a single task in retention and creating three independent blocked groups, varying amounts of retroactive inhibition were produced. This isolated the effects of retroactive inhibition on blocked compared to control and random subjects' retention. The Acquisition Group x Retention Trials interaction indicated that random and BL-without subjects had shorter reaction time than BL-18 and BL-36 subjects. Thus, blocked subjects with retroactive inhibition exhibited a retention deficit compared to BL-without subjects. The results support previous contextual interference findings and suggest that retroactive inhibition influences the retention deficits demonstrated by blocked compared to random subjects in typical contextual interference investigations.

The aim of this study was to observe the correlation between liver biopsy bleeding time, prothrombin time ratio and platelet count. The subjects were 51 consecutive patients referred for laparoscopic liver biopsy. The intervention was laparoscopy under local anaesthetic and liver biopsy with observation of post biopsy bleeding time. No correlation was found between observed liver biopsy bleeding time and platelet count or prothrombin time ratio. Thus, mild to moderate coagulopathy does not appear to be associated with prolonged bleeding following liver biopsy. Equally, normality of these coagulation studies does not indicate an absence of risk for post liver biopsy bleeding.

The insertion of a transjugular intrahepatic portasystemic stent shunt (TIPSS) was evaluated in 22 patients with recurrent upper gastrointestinal haemorrhage related to portal hypertension (bleeding from oesophageal varices 10, gastric varices six, portal hypertensive gastropathy six). TIPSS was successfully performed electively in 15 patients and as an emergency in three patients. Twelve patients have had no further admissions with bleeding after TIPSS. Single episodes of bleeding were noted in six patients after TIPSS associated with shunt thrombosis (two), intimal hyperplasia within the shunt (two), and shunt migration (one). Another patient presented with reaccumulated ascites suggesting poor shunt function but died from massive variceal haemorrhage before further assessment could be performed. There was one death related to the procedure. Two patients developed encephalopathy after TIPSS, in one patient this was controlled by the insertion of a smaller diameter stent within the existing TIPSS. Several complications arose in earlier patients that have not recurred after modification of the initial technique. TIPSS can be life saving and is effective in controlling variceal haemorrhage and rebleeding from oesophageal or gastric varices and portal hypertensive gastropathy. Larger and longer term studies are required, however, to define the role of TIPSS in the overall management of such patients.

Transjugular intrahepatic portosystemic stent shunt (TIPSS) is a new percutaneous technique for reducing portal venous pressure. We attempted TIPSS in six patients with recurrent bleeding for oesophageal or gastric varices between July 1991 and January 1992 with success in five. There have been no deaths. One patient re-bled after TIPSS. His portal pressure was found to be elevated persistently indicating an inadequate shunt. Following further dilatation of the shunt, portal pressure fell to a satisfactory level and bleeding has not recurred. No bleeding episodes have occurred in the other patients following successful TIPSS. Our series contributes to the growing body of experience which suggests that TIPSS is a safe and effective treatment for recurrent variceal bleeding.

Understanding the morphological, movement, and biomechanical characteristics that influence rearfoot motion during lateral movements is necessary for footwear design and for the determination of injury mechanisms. The purpose of this study was to identify factors related to rearfoot kinematics during a lateral braking movement. Seven highly skilled male tennis players performed 24 trials of side shuffle movements at various speeds. A rear view of the right leg performing a braking step onto a force platform was filmed. The neutral-O landing style was most commonly demonstrated. Average movement velocity, foot velocity at touchdown, and body mass were variables demonstrating weak or nonsignificant correlations with the rearfoot parameters. Although structural inversion was correlated significantly with the maximum rearfoot angle and velocity (r = -0.52 and -0.69), the results were affected by movement speed and sample size. The biomechanical characteristics displayed the greatest influence on the various rearfoot kinematic parameters. The magnitude of the significant (P less than 0.0001) correlations generally decreased in the following order: maximum horizontal and vertical force gradients, corresponding times to the maximum gradient values, maximum horizontal and vertical forces, and the corresponding times to maximum forces. In conclusion, the gradient-associated parameters were the most useful biomechanical parameters for predicting changes in rearfoot kinematics.

In experimentally produced alcoholic fatty liver microsomal fatty acid composition was measured using gas chromatography. The results showed an increase in linoleic acid (18:2, n-6) and hexadecaenoic acid (22:6, n-3) and a decrease in arachidonic acid (20:4, n-6) in alcohol-fed rats. Using high performance liquid chromatographic separation of radiolabelled substrate and products, delta 9, delta 6 and delta 5 desaturase enzymes were assayed. The activity of delta 9 and delta 5 desaturase was decreased in alcohol-fed rats and delta 6 desaturase activity was similar in control and alcohol-fed groups. These results indicated there was no causal relationship between desaturase activity and membrane fatty acid changes. Increased amounts of eicosatrienoic acid (20:3, n-9) in rats fed less than 5% fat were observed in both control and alcohol-fed rats. The results indicated that essential fatty acid deficiency was not due to alcohol consumption.

1. Patients with a history of alcohol abuse were studied by 31P n.m.r. spectroscopy of the liver in vivo, and the results were related to the pattern of disease assessed by standard biochemical and histological techniques. 2. The ratios of metabolites measured from the 31P n.m.r. spectra were abnormal in patients with alcoholic hepatitis but not in those with fatty change or cirrhosis in the absence of hepatitis. In particular, the levels of phosphomonoesters were raised, with respect either to Pi, or to adenosine 5'-triphosphate. The level of phosphomonoesters showed a significant positive correlation with the severity of alcoholic hepatitis, assessed by histology. 3. The ratio of Pi to adenosine 5'-triphosphate was used as a measure of the energy status of the hepatocytes, and was unchanged between patients and controls.

The activities of coproporphyrinogen oxidase, protoporphyrinogen oxidase and ferrochelatase have been assayed in human liver biopsies using recently developed highly sensitive specific enzyme assays. The specific activities (nmol/min/mg protein) in controls were 0.010 +/- 0.003 (mean +/- S.D., n = 11), 0.18 +/- 0.07 (n = 9) and 0.062 +/- 0.022 (n = 8), respectively. The total activities (mumol/min/liver) were determined, using ultrasound to determine liver volumes, and were 2.6 +/- 0.6 (n = 5), 36.6 +/- 13.9 (n = 6) and 14.2 +/- 5.4 (n = 3), respectively. Both specific and total enzyme activities in alcoholics with fatty liver were not significantly different from normal controls. Decreased protoporphyrinogen oxidase activity (0.08 nmol/min/mg protein or 20.2 mumol/min/liver) was found in two patients with variegate porphyria. In a patient with erythrohepatic protoporphyria a reduction of the ferrochelatase activity (0.01 nmol/min/mg protein) was demonstrated.

1. Chronic (5 weeks) alcohol-fed and isocaloric glucose pair-fed control rats had similar body weights, liver weights and liver protein contents. 2. Hepatic esterified cholesterol and triacylglycerol levels were two- to three-fold higher in alcohol-fed rats than in controls. 3. Hepatic cholesterol synthesis rates measured in vivo with 3H2O were significantly reduced in alcohol-fed rats. 4. Hepatic 3-hydroxy-3-methylglutaryl-CoA reductase (NADPH) (EC 1.1.1.34) activity was increased and the apparent Km for 3-hydroxymethyl-3-glutaryl-CoA was decreased in alcohol-fed rats. 5. Hepatic acyl-CoA:cholesterol acyltransferase (cholesterol acyltransferase; EC 2.3.1.26) activity was significantly increased in alcohol-fed rats. 6. These results indicate that there is no direct relationship between 3-hydroxy-3-methylglutaryl-CoA reductase activity and sterol synthesis in liver of alcohol-fed rats.