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The effects of hyperammonemia on brain function have been studied in three different experimental models in the rat: acute liver ischemia, urease-treated animals and methionine sulfoximine-treated animals. To quantify the development of encephalopathy, clinical grading and electroencephalographic spectral analysis were used as indicators. In all three experimental models brain ammonia concentrations increased remarkably associated with comparable increases in severity of encephalopathy. Furthermore, in vivo 1H-nuclear magnetic resonance spectroscopy of a localized cerebral cortex region showed a decrease in glutamate concentration in each of the aforementioned experimental models. This decreased cerebral cortex glutamate concentration was confirmed by biochemical analysis of cerebral cortex tissue post mortem. Furthermore, an increase in cerebral cortex glutamine and lactate concentration was observed in urease-treated rats and acute liver ischemia rats. As expected, no increase in cerebral cortex glutamine was observed in methionine sulfoximine-treated rats. These data support the hypothesis that ammonia is of key importance in the pathogenesis of acute hepatic encephalopathy. Decreased availability of cerebral cortex glutamate for neurotransmission might be a contributing factor to the pathogenesis of hyperammonemic encephalopathy. A surprising new finding revealed by 1H-nuclear magnetic resonance spectroscopy was a decrease of cerebral cortex phosphocholine compounds in all three experimental models. The significance of this finding, however, remains speculative.

genesis of HE. [2][3][4][5][6][7] Moreover, elevated brain glutamine concenThe aim of this study was to investigate the possible trations can induce cell swelling, resulting in brain edema, 8,9 role of N-methyl-D-aspartate (NMDA)-receptor overaca terminal event in patients with fulminant hepatic failure. creased CSF glutamate and aspartate concentrations This study was designed to investigate the role of NMDAand increased ICP and brain water content. Memantine receptor activity in hyperammonemia-induced encephalopaadministration in AI-PCS and LIS rats resulted in a sigthy and liver ischemia-induced HE, two experimental rat nificant improvement in clinical grading and less slowmodels that both are associated with intracranial hypertening of EEG activity (P õ .05), and smaller increases in sion. Therefore, the noncompetitive NMDA-receptor antago-CSF glutamate (P õ .05) concentrations. Moreover, ICP nist memantine 21-24 was administered to portacaval-shunted and brain water content were significantly lower in (PCS) rats with an ammonium-acetate infusion and to rats memantine-treated AI-PCS rats than in untreated AIwith complete liver ischemia. The severity of encephalopathy PCS rats (P õ .05). Memantine had no significant effect was quantified by clinical grading and electroencephalogram on ICP and brain water content in LIS rats, and on am-(EEG) spectral analysis. Plasma concentrations of ammonia monia concentrations in both models. These results indiand memantine, and CSF concentrations of amino acids, were cate that NMDA-receptor activation might be involved assessed. Intracranial pressure was measured with a presin the pathogenesis of hyperammonemia-induced ensure transducer connected to a cisterna magna cannula, and, cephalopathy and of acute hepatic encephalopathy in addition, brain water content was assessed at the end of caused by LIS. (HEPATOLOGY 1997;25:820-827.) the experiment.

Both increased gamma-aminobutyric acid (GABA)-ergic and decreased glutamatergic neurotransmission have been suggested relative to the pathophysiology of hepatic encephalopathy. This proposed disturbance in neurotransmitter balance, however, is based mainly on brain tissue analysis. Because the approach of whole tissue analysis is of limited value with regard to in vivo neurotransmission, we have studied the extracellular concentrations in the cerebral cortex of several neuroactive amino acids by application of the in vivo microdialysis technique. During acute hepatic encephalopathy induced in rats by complete liver ischemia, increased extracellular concentrations of the neuroactive amino acids glutamate, taurine, and glycine were observed, whereas extracellular concentrations of aspartate and GABA were unaltered and glutamine decreased. It is therefore suggested that hepatic encephalopathy is associated with glycine potentiated glutamate neurotoxicity rather than with a shortage of the neurotransmitter glutamate. In addition, increased extracellular concentration of taurine might contribute to the disturbed neurotransmitter balance. The observation of decreasing glutamine concentrations, after an initial increase, points to a possible astrocytic dysfunction involved in the pathophysiology of hepatic encephalopathy.

A major roadblock to the application of bioartificial livers is the need for a human liver cell line that displays a high and broad level of hepatic functionality. The human bipotent liver progenitor cell line HepaRG is a promising candidate in this respect, for its potential to differentiate into hepatocytes and bile duct cells. Metabolism and synthesis of HepaRG monolayer cultures is relatively high and their drug metabolism can be enhanced upon treatment with 2% dimethyl sulfoxide (DMSO). However, their potential for bioartificial liver application has not been assessed so far. Therefore, HepaRG cells were cultured in the Academic Medical Center bioartificial liver (AMC-BAL) with and without DMSO and assessed for their hepatic functionality in vitro and in a rat model of acute liver failure. HepaRG-AMC-BALs cultured without DMSO eliminated ammonia and lactate, and produced apolipoprotein A-1 at rates comparable to freshly isolated hepatocytes. Cytochrome P450 3A4 transcript levels and activity were high with 88% and 37%, respectively, of the level of hepatocytes. DMSO treatment of HepaRG-AMC-BALs reduced the cell population and the abovementioned functions drastically. Therefore, solely HepaRG-AMC-BALs cultured without DMSO were tested for efficacy in rats with acute liver failure (n = 6). HepaRG-AMC-BAL treatment increased survival time of acute liver failure rats ∼50% compared to acellular-BAL treatment. Moreover, HepaRG-AMC-BAL treatment decreased the progression of hepatic encephalopathy, kidney failure, and ammonia accumulation. These results demonstrate that the HepaRG-AMC-BAL is a promising bioartificial liver for clinical application.

With an increasing number of paediatric and adolescent athletes presenting with injuries due to overuse, a greater demand is put on clinicians and radiologists to assess the specific type of injury. Repetitive forces applied to the immature skeleton cause a different type of injury than those seen in adults due to the differences in vulnerability of the musculoskeletal system, especially at the site of the growth cartilage. Intrinsic and extrinsic risk factors all play a role in the development of overuse injuries. MRI plays a key role in imaging overuse injuries due to its high potential for depicting cartilaginous and softtissue structures. Sport-specific biomechanics are described, since this knowledge is essential for adequate MRI assessment. An overview of several sport-related injuries is presented, based on anatomical location.

This article examines why people may blame innocent victims of robbery or sexual assault. We propose that in experiential mind-sets associative links are formed between the victim and the negative event. As the creation of such links is independent of explicit beliefs, people in experiential mind-sets produce negative reactions to the victim independent of their just-world beliefs. Rationalistic mind-sets, however, instigate propositional and consistency-based reasoning. For people who strongly endorse just-world beliefs (such as people who have strong predispositions to believe that the world is just or whose just-world beliefs have been threatened strongly), learning about an innocent victim creates a logically inconsistent system of beliefs. This inconsistency can be resolved by blaming the victim. For people who only weakly endorse just-world beliefs, there is no inconsistency in the first place and therefore no need to blame the victim. Two experiments support this line of reasoning.

Interleukin-6 (IL-6) administration to human subjects or experimental animals induces changes in thyroid hormone metabolism resembling those in the sick euthyroid syndrome. Furthermore, the decrease in serum T3 during illness is significantly related to serum IL-6 concentrations. These findings suggest, but do not prove, a causal role for IL-6 in the development of the low T3 syndrome. The aim of the present study was to evaluate the role of IL-6 in the development of the sick euthyroid syndrome in IL-6 knock-out (IL-6(-/-)) mice compared to that in wild-type mice (IL-6(+/+)). Illness was induced in IL-6(-/-) and IL-6(+/+) mice by 1) administration of bacterial endotoxin (LPS), 2) infection with Listeria monocytogenes, and 3) turpentine injection in both hind limbs. Food intake was kept similar in both groups in all three experiments. Serial measurements were made of serum IL-6, tumor necrosis factor-alpha, T3, T4, corticosterone, and liver 5'-deiodinase (5'-DI) messenger RNA (mRNA) for 24 h (LPS), 96 h (L. monocytogenes), and 48 h (turpentine). Serum IL-6 increased in response to all stimuli in IL-6(+/+) mice, but not in IL-6(-/-) mice. Serum tumor necrosis factor-alpha was induced by LPS in both groups to a similar extent, but did not rise after L. monocytogenes or turpentine administration. Serum T3 and T4 decreased after all three stimuli. The decrease in serum T4 in IL-6(-/-) was similar to that in IL-6(+/+) mice. The decrease in serum T3, however, was smaller in the IL-6(-/-) mice than in the IL-6(+/+) mice; T3 levels were 1.56 +/- 0.29 and 0.99 +/- 0.15 nmol/liter, respectively, 24 h after LPS treatment (P < 0.01), 2.39 +/- 0.17 and 1.75 +/- 0.24 nmol/liter 96 h after L. monocytogenes treatment (P < 0.01), and 1.46 +/- 0.18 and 1.10 +/- 0.25 nmol/liter 48 h after turpentine treatment (P < 0.05). The smaller fall in serum T3 in IL-6(-/-) mice could not be attributed to differences in the severity of the induced illness, food intake, or corticosterone response, which were all similar in IL-6(-/-) mice and IL-6(+/+) mice. Liver 5'-deiodinase mRNA decreased after all three stimuli; the decrease after LPS and L. monocytogenes infection was smaller in the IL-6(-/-) mice, but the difference in IL-6(+/+) mice just failed to reached statistical significance. Liver 5'-deiodinase activity after turpentine injection administration decreased in the wild-type animals by 36%, but did not change in the knock-out mice. In conclusion, acutely induced illness generates the low T3 syndrome, which is less marked in IL-6 knock-out mice than in wild-type mice. The data suggest a causal role of IL-6 in the development of the low T3 syndrome.