Ex vivo normothermic machine perfusion and viability testing of discarded human donor livers.

In contrast to traditional static cold preservation of donor livers, normothermic machine perfusion may reduce preservation injury, improve graft viability and potentially allows ex vivo assessment of graft viability before transplantation. We have studied the feasibility of normothermic machine perfusion in four discarded human donor livers. Normothermic machine perfusion consisted of pressure and temperature controlled pulsatile perfusion of the hepatic artery and continuous portal perfusion for 6 h. Two hollow fiber membrane oxygenators provided oxygenation of the perfusion fluid. Biochemical markers in the perfusion fluid reflected minimal hepatic injury and improving function. Lactate levels decreased to normal values, reflecting active metabolism by the liver (mean lactate 10.0 ± 2.3 mmol/L at 30 min to 2.3 ± 1.2 mmol/L at 6 h). Bile production was observed throughout the 6 h perfusion period (mean rate 8.16 ± 0.65 g/h after the first hour). Histological examination before and after 6 h of perfusion showed well-preserved liver morphology without signs of additional hepatocellular ischemia, biliary injury or sinusoidal damage. In conclusion, this study shows that normothermic machine perfusion of human donor livers is technically feasible. It allows assessment of graft viability before transplantation, which opens new avenues for organ selection, therapeutic interventions and preconditioning.

Activation of neurotrophin-3 receptor TrkC induces apoptosis in medulloblastomas.

Elevated expression of the neurotrophin-3 (NT-3) receptor TrkC by childhood medulloblastomas is associated with favorable clinical outcome. Here, we provide evidence that TrkC is more than simply a passive marker of prognosis. We demonstrate that: (a) medulloblastomas undergo apoptosis in vitro when grown in the presence of NT-3; (b) overexpression of TrkC inhibits the growth of intracerebral xenografts of a medulloblastoma cell line in nude mice; and (c) trkC expression by individual tumor cells is highly correlated with apoptosis within primary medulloblastoma biopsy specimens. TrkC-mediated NT-3 signaling promotes apoptosis by activating multiple parallel signaling pathways and by inducing immediate-early gene expression of both c-jun and c-fos. Considered collectively, these results support the conclusion that the biological actions of TrkC activation affect medulloblastoma outcome by inhibiting tumor growth through the promotion of apoptosis.

Neurotrophins in cerebellar granule cell development and medulloblastoma.

Medulloblastomas may be derived from granule cells of the developing cerebellum. Children with tumors expressing high levels of the neurotrophin-3 receptor, TrkC, have a more favorable outcome. During development, TrkC is expressed in the most mature granule cells. Favorable medulloblastomas may be derived from more highly differentiated granule cells.

The effects of dexamethasone on plasma homovanillic acid and 3-methoxy-4-hydroxyphenylglycol. Evidence for abnormal corticosteroid-catecholamine interactions in major depression.

We investigated the possible interactions between corticosteroids and catecholamines in depression by studying the effects of the synthetic glucocorticoid dexamethasone on plasma levels of homovanillic acid (HVA) and 3-methoxy-4-hydroxyphenylglycol (MHPG) in a group of depressed patients and normal controls. In comparison with metabolite levels on a control day, normal controls showed a significant dexamethasone-induced increase in the plasma HVA level and a trend toward a decrease in the plasma MHPG level at 4 PM following dexamethasone administration (1 mg orally at 11 PM). Conversely, depressed patients, particularly those with psychotic features, showed a significant dexamethasone-induced increase in the plasma MHPG level and a blunting of the plasma HVA response relative to the normal controls. Dexamethasone-induced increases in the plasma MHPG level were directly correlated with the severity of depressive symptoms and with postdexamethasone cortisol levels in the depressed patients. These data suggest abnormal corticosteroid-catecholamine interactions in depression and, specifically, in depressed patients with psychotic features.

A behavioral analysis of the effects of amphetamine on play and locomotor activity in the post-weaning rat.

Amphetamine has been shown to canalize or direct the activity of a young rat towards ethologically relevant stimuli. In the five-day-old, amphetamine increases the speed of approach to the nipple of an anesthetized dam; in the 15-day-old, amphetamine increases motor activity and directs it toward an anesthetized adult, however, in the juvenile rat amphetamine reportedly disrupts species-specific behaviors such as huddling and play. The present experiments further assessed the effects of amphetamine in the post-weaning rat by measuring drug-induced behaviors in the presence of an alert and anesthetized companion. In Experiment 1, subjects were videotaped in the presence of an alert non-treated, same-age rat and components of play, a predominant behavior of the post-weaning rat, were recorded. Results confirmed previous reports that low doses of amphetamine (0.5 mg/kg) disrupt play behavior, however, in the present experiment higher doses of amphetamine (1.0 mg/kg) did not disrupt the percentage of time spent in play. Further analysis of drug-induced behavior revealed that the 1.0 mg/kg amphetamine-injected rat engaged in play with the companion, although the drug-treated animal did exhibit marked alterations in the flexibility of its motor patterns. The second experiment confirmed that amphetamine did not disrupt the amount of time a juvenile rat spent with an anesthetized age-mate. In fact, amphetamine-induced activity was directed towards the anesthesized same-age rat. Following amphetamine treatment, all subjects were active nearly 100% of the observation period whether they were tested alone or in the presence of an anesthetized same-age rat.(ABSTRACT TRUNCATED AT 250 WORDS)

Dexamethasone increases plasma HVA but not MHPG in normal humans.

Several recent studies in animals and man indicate that corticosteroids may alter catecholaminergic activity in both the peripheral and central nervous systems. We administered 1 mg of the synthetic glucocorticoid, dexamethasone, to 12 drug-free healthy volunteers and measured plasma homovanillic acid (HVA) and 3-methoxy-4-hydroxyphenylglycol (MHPG). Dexamethasone was administered at 11 p.m. and blood was collected at 4 p.m. on the preceding and subsequent days. Dexamethasone administration resulted in a significant increase in plasma HVA but did not consistently affect MHPG. All subjects showed a suppression of serum cortisol to values less than 5 micrograms/dl while prolactin levels were unaltered. In an additional group of nine volunteers, we administered 2 mg of dexamethasone and observed a similar increase in plasma HVA without change in plasma MHPG, indicating a selective effect on dopamine metabolism. Implications of these findings for an understanding of the neurochemical and behavioral changes seen with steroid administration and in explaining previous results on plasma MHPG/HVA ratios in delusional depression are discussed.

Animal models of self-destructive behavior and suicide.

In this article we have addressed selected aspects of animal models that may have ramifications in our understanding of suicide and human self-destructive behavior. It should be kept in mind that these human behaviors have many determinants. In considering animal models, we do not propose that similar behaviors necessarily have the same causation nor that a particular experimental manipulation that produces a behavioral syndrome in one species will produce that response in another species. Even if environmental conditions or the resulting behaviors vary for different species, the biochemical intermediaries may be similar. The simplification inherent in the laboratory modeling of an aspect of human behavior should not mean that the complexity of the human syndrome be forgotten. However, if a simple explanation can account for the production of a particular behavioral syndrome in animals, it can help to structure our thoughts regarding the etiology of the behavior in humans. The ethologic observations discussed in this article may help to place human self-destructive behavior in a continuum with that of animals in the wild. Although care should be given to drawing direct parallels, the clear conclusion is that humans are not alone in exhibiting self-initiated behaviors that ultimately produce self-harm or death. Whereas laboratory models have been extensively used for modeling psychiatric illnesses or for producing specific pharmacologic manipulations of the CNS, surprisingly little attention has been given to the modeling of self-destructive behaviors themselves. Emphasis on self-destructive behaviors, as well as on their biologic and genetic underpinnings, represent an important future direction for work on animal models in psychiatry.