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K D Mullen

Publications and source records attributed to K D Mullen.

At least 37 records · Page 2Linked to original sources
PubMed1997

Precipitation of overt encephalopathy in the portacaval shunted rat: towards the development of an adequate model of chronic portal systemic encephalopathy.

OBJECTIVE: To assess the feasibility of developing a model of overt portal-systemic encephalopathy (PSE) in rats with a surgically constructed portacaval anastomosis (PCA). DESIGN: The ability of increasing the load of nitrogenous substances in the gastrointestinal tract and/or further decreasing hepatocellular function to induce overt encephalopathy in rats with a PCA was determined. METHODS: The load of nitrogenous substances in the gastrointestinal tract was increased by feeding a pure horse-meat diet or by gavaging with blood. Partial hepatectomy and the induction of cirrhosis were used to decrease hepatocellular function further. The severity of encephalopathy was assessed using a neurobehavioural scale. RESULTS: Overt encephalopathy was not induced in rats by a PCA alone, by a PCA plus a horse-meat diet, by a PCA plus induction of cirrhosis, or by a PCA plus a 50% hepatectomy. Predominantly mild, but overt, encephalopathy was induced in rats with a PCA alone by gavaging with blood and a higher incidence of more severe overt encephalopathy was induced in rats with a PCA combined with either cirrhosis or partial hepatectomy by gavaging with blood. Although these models of PSE were associated in some instances with plasma ammonia concentrations about 25 times higher than normal, no seizures were observed. CONCLUSION: A syndrome that resembles overt PSE in humans can be induced in the rat with a PCA by further reducing hepatocellular function and also gavaging with blood. Although the rat with a PCA has been. extensively used as a model in studies relating to the pathogenesis of PSE, a syndrome resembling overt PSE in humans cannot readily be induced in rats with a PCA.

Ammonia↗
PubMed1996

Pathogenesis of hepatic encephalopathy: potential future approaches.

Attempting to forecast future trends in research is difficult enough in any area but is well nigh impossible with the volatile field of hepatic encephalopathy (HE). Undaunted in this review it is suggested that more frequent use of intact animal models of HE to probe the pathogenesis of HE will occur with newly developed pharmacological agents. This process would be greatly facilitated by wide acceptance of a discrete number of reproducible animal models of this syndrome. Brief comments are made on the current status on some of the current hypotheses. Greater utilization of patients with subclinical HE for clinical studies will occur. Continuing interest in nuclear magnetic resonance imaging and spectroscopy findings peculiar to HE will be seen over the next decade.

Animals↗
PubMed1996

Hepatic encephalopathy.

The syndrome of hepatic encephalopathy has mystified physicians since the time of Hippocrates, and it continues to do so. It is difficult to succinctly define, diagnose with certainty, or attempt to explore its pathogenesis. The literature on this topic is confusing and often contradictory. Nevertheless, very effective empirical therapy has been devised for this syndrome. We discuss selected aspects of diagnosis, pathogenesis, clinical manifestations, and treatment of hepatic encephalopathy. Emphasis is placed on the three-pronged clinical strategy to manage hepatic encephalopathy that encompasses both diagnostic and treatment measures. The burgeoning area of subclinical hepatic encephalopathy is discussed in more detail than in most reviews of this topic. We also propose a new term for the field-acute liver failure-associated hepatic encephalopathy (ALFA-HE)-to replace the unsatisfactory older term, fulminant hepatic failure.

Hepatic Encephalopathy↗
PubMed1994

Animal models of hepatic encephalopathy and hyperammonemia.

Animal models of chronic liver disease with hyperammonemia are currently available to investigators. Two in particular have been utilized extensively. Carbon tetrachloride induced (CCl4) cirrhosis in the rat and portacaval shunt in the same species and other animals particularly the dog. In regards to hepatic encephalopathy, however, the CCl4 cirrhosis rat model seems to display few behavioral changes unless very advanced decompensated cirrhosis is produced. Further work should be done on this model to verify the development of encephalopathy and to improve reproducibility. The portacaval shunt rat on the other hand clearly has a consistent albeit subtle set of behavioral changes. Recent improvements in detecting these changes and more importantly showing reversal or improvement by neomycin or a low protein diet are a major advance. Hopefully, more laboratories will be able to reproduce this reversible change in behavior. Experiences gained from 7 years of using the portacaval shunt rat and other models of liver disease are described.

Ammonia↗
PubMed1994

Pathogenetic mechanisms of acute hepatic encephalopathy.

With the advent of liver transplantation as an accepted therapy for end-stage liver disease, increasing numbers of patients with severe hepatic dysfunction require ICU stabilization and treatment of associated complications. Of these, acute hepatic encephalopathy remains an important cause of morbidity and mortality. We review recent findings concerning interactions between the damaged liver and the brain that may have direct clinical implications in the management of hepatic encephalopathy in the critically ill.

Acute Disease↗
PubMed1994

Decrease in serum levels of markers of hepatic connective tissue turnover during and after treatment of chronic hepatitis B with interferon-alpha.

Interferon-alpha induces remission in 30% to 40% of patients with chronic hepatitis B, but its effect on hepatic connective tissue turnover has not been well documented. We studied the changes in serum procollagen III propeptide and laminin-P1 peptide (Lam-P1) in 33 patients with chronic hepatitis B (11 nontreated controls and 22 treated patients) during a 4-mo randomized trial of interferon-alpha. Liver biopsy specimens were obtained at the start of treatment and 12 mo later. Liver biochemical tests, procollagen III propeptide, laminin-P1 peptide and hepatitis B virus DNA polymerase were determined before treatment with interferon was begun (mo -3), at the initiation (0 time) and completion of treatment (mo 4) and also at 8, 12 and 18 mo. Treated patients were classified as "responders" and "nonresponders" on the basis of clearance of HBV e antigen from serum. There were no significant changes in the control group, whereas the responders had persistent decreases in ALT, AST, hepatitis B virus dna polymerase, procollagen III propeptide and laminin-P1 peptide. The nonresponders had transient ALT, AST and hepatitis B virus dna polymerase reductions that returned toward baseline levels during follow-up, but procollagen III propeptide and laminin-P1 peptide persisted below the baseline at mo 18. Significant correlations between procollagen III propeptide and laminin-P1 peptide with ALT, AST and liver histologic specimens were noted at baseline but not after 12 mo. Changes in procollagen III propeptide levels also correlated with changes in AST, ALT and liver histologic specimens.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1994

Reversal of behavioral changes in rats subjected to portacaval shunt with oral neomycin therapy.

The portacaval shunt rat is often used as a model of human portal-systemic encephalopathy, but its relevance to human portal-systemic encephalopathy remains uncertain. Specifically, it has not been demonstrated that the behavioral changes seen in this model respond to measures known to improve portal-systemic encephalopathy in human subjects. Accordingly, the aim of this study was to establish whether neomycin (an effective treatment for portal-systemic encephalopathy in human beings) added to the drinking water of rats subjected to portacaval shunt reversed or ameliorated the reduction in spontaneous motor activity, which represents a measure of encephalopathy in this animal model. A randomized, placebo-controlled crossover design was used, with each animal serving as its own control. After establishment of baseline activities, 12 rats with portacaval shunt and 12 sham-operated rats were divided into two equal groups: Group A animals received neomycin for 1 wk; this was followed by 1 wk off neomycin; in group B rats, the sequence was reversed. Spontaneous intake of neomycin for 7 days at doses comparable to human usage (0.1 to 0.2 gm/kg/day) was associated with a significant increase in spontaneous motor activity in rats subjected to portacaval shunt (26.4% in group A, 66.3% in group B; p < 0.01 for each protocol) with no significant effect in sham-operated animals. Withdrawal of neomycin resulted in reversal of this effect in group A rats subjected to portacaval shunt. Similar significant improvements for exploratory activity as measured on the basis of nose-hole pokes was also seen in rats subjected to portacaval shunt and given neomycin.(ABSTRACT TRUNCATED AT 250 WORDS)

Ammonia↗
PubMed1994

Gender-dependent reduction of spontaneous motor activity and growth in rats subjected to portacaval shunt.

Alterations in behavior are frequently described in rats subjected to portacaval shunt. Previous work has reported reduced spontaneous motor activity in various settings (nighttime, red light, decreased illumination) in this animal model. We investigated this phenomenon in rats of both genders subjected to portacaval shunt to determine whether our previously observed divergent growth patterns (males reduced, females unchanged) had any impact on the alterations in spontaneous motor activity in this model. Dietary intake, growth, motor activity and serum ammonia and amino acid concentrations were measured, in addition to final liver and spleen weights, in each animal after 3 to 4 wk of observation. Our results reconfirm the differential impact of portacaval shunt on growth in male (35% reduction p < 0.01) but not female rats (5% reduction, NS) compared with their respective-gender sham-operated controls. In addition, spontaneous motor activity was significantly reduced in male (congruent to 50%, p = 0.01) but not female rats subjected to portacaval shunt. The reduction of activity in male rats subjected to portacaval shunt did not correlate with any of the measured biochemical data or calculated nutritional/growth parameters. Thus we observed gender-dependent reduction in spontaneous motor activity after portacaval shunt in the rat. The mechanism for this phenomenon is unknown, but it is easily investigated with this reproducible model.

Amino Acids↗
PubMed1993

Studies of "endogenous" benzodiazepine in human hepatic encephalopathy.

As will be discussed by Dr E.A. Jones based on observations in animal models of hepatic encephalopathy (HE) in 1984 we commenced our studies on the possible role of "endogenous" benzodiazepines (BZs) in human HE in 1986. Unlike animals our initial studies in humans with HE were complicated by the frequent intake of prescription BZs by these patients. Re-education of our staff on the appropriate use of BZs in patients with liver disease and a carefully devised system to exclude patients who have received prescription BZs in the 3 months preceding hospital admission was instigated before our studies could commence. Initially, we examined CSF of patients with HE for the presence of BZ-like activity using a radiometric assay. Our findings of significantly increased activity have since been confirmed by other investigators. Subsequently we discovered fairly large quantities of BZs in blood and urine of these patients, the level of which correlated with the degree of severity of HE. The ultimate finding that this BZ-like activity was due to diazepam, desmethyldiazepam and some other 1-4 benzodiazepine compounds again raised the possibility that our findings were due to occult ingestion of commercially synthesized BZs even though similar findings were made in animal models of HE. Concurrently with this work it became apparent that the food cycle contains trace amounts of the same BZs. However, the levels of "natural BZs" in food cannot yet explain the high levels of BZs seen in patients with HE. The source for this high level of BZs is currently our main area of research.

Animals↗
PubMed1992

In vivo differences between the turnover rates of leucine and leucine's ketoacid in stable cirrhosis.

Based on urinary nitrogen excretion, previous studies have indicated increased protein breakdown rates in cirrhosis. However, studies using [1-13C]-leucine infusion methodology have found normal protein breakdown rates. Because abnormal partitioning between extracellular and intracellular leucine exists in cirrhosis, plasma enrichment of leucine's keto acid (KIC), a marker of intracellular leucine, may more accurately reflect protein metabolism than plasma [1-13C]leucine enrichment. Therefore, protein breakdown and oxidation were calculated using both [1-13C]leucine and [1-13C]KIC and compared with urinary nitrogen excretion in seven cirrhotics and seven matched controls after an overnight fast. The ratio of KIC and leucine plasma enrichment was decreased (P less than 0.001) in cirrhosis because of lower KIC enrichment (P less than 0.006). Cirrhotics had increased rates of protein breakdown (P less than 0.006) and protein oxidation (P less than 0.05) based on KIC (P less than 0.006) but not leucine enrichment. In controls, protein oxidation calculated from urinary nitrogen excretion did not differ from KIC results (0.88 +/- 0.08 vs. 0.83 +/- 0.06) but was higher than the leucine method (0.88 +/- 0.08 vs. 0.73 +/- 0.05; P less than 0.01). However, in cirrhotics protein oxidation based on urinary nitrogen was lower than the KIC methodology (P less than 0.01). Therefore, cirrhotics have accelerated rates of protein breakdown and oxidation associated with increased extrarenal nitrogen loss. Furthermore, these results suggest abnormal leucine transport across cell membranes.

Adult↗