Review: Recent advances in liver transplantation

Liver transplant is a life-saving treatment with 1-year and 5-year survival rates of 90% and 70%, respectively. However, organ demand continues to exceed supply, such that many patients will die waiting for an available organ. This article reviews for the general gastroenterologist the latest developments in the field to reduce waiting list mortality and maximise utilisation of available organs. The main areas covered include legislative changes in organ donation and the new ‘opt-out’ systems being rolled out in the UK, normothermic machine perfusion to optimise marginal grafts, a new national allocation system to maximise benefit from each organ and developments in patient ‘prehabilitation’ before listing. Current areas of research interest, such as immunosuppression withdrawal, are also summarised.     

Suppression of growth of PHA-stimulated human lymphocytes by a novel steroid (RU 28 362) lacking the 21-OH group

RU 28 362 is a novel synthetic steroid (lacking the 21-OH group) which reacts exclusively with the glucocorticoid receptor. It is therefore chemically different from the other natural and synthetic glucocorticoids in common use which also bind to a lesser extent to receptors for other classes of steroids. Aspects of the immunosuppressive effect of RU 28 362 were studied by comparing its suppressive effects on PHA-stimulated growth of human lymphocytes with those of hydrocortisone, betamethasone and the inactive analogue, 21-deoxyhydrocortisone. RU 28 362 was more potent than either hydrocortisone or betamethasone, but all three glucocorticoids had a parallel dose-response curve in suppression of the increase in cell volume that occurs with activation during the first day in culture. In studies on the time of appearance and density of IL-2 receptors during the first 3 days in culture, RU 28 362 was also somewhat more inhibitory and had a steeper dose-response curve than hydrocortisone or betamethasone. RU 28 362 was much more inhibitory and had a steeper dose-response curve than either hydrocortisone or betamethasone in inhibiting [3H]-TdR incorporation by 3-day PHA stimulated cultures. 21-deoxyhydrocortisone did not inhibit any aspect of PHA-stimulated lymphocyte growth.     

Discrimination of MHC-derived odors by untrained mice is consistent with divergence in peptide-binding region residues

Genes of the major histocompatibility complex (MHC) play a central role in immune recognition, yet they also influence the odor of individuals. Mice can be trained to distinguish odors mediated by classical MHC loci; however, training can introduce confounding behavioral artifacts. This study demonstrates that mice can distinguish some, but not all, naturally occurring allelic variants at classical MHC loci without prior training. This result suggests that MHC-disassortative mating preferences might operate by means of small MHC-based odor differences, and could therefore contribute to diversifying selection acting on MHC loci. Here we show that odors of two MHC mutant mouse strains (bm1 and bm3) can be distinguished, even after genetic background is controlled by intercrossing strains. These two strains differ by five amino acids, three of which are predicted to chemically contact peptides bound to the peptide-binding region (PBR), the site of antigen presentation for T cell recognition. However, the odors of neither bm1 nor bm3 were distinguished from their parental B6 haplotype after randomizing genomic background, despite discrimination of pure-bred B6 and bm1 strain odors. These combined results suggest that (i) there may be an MHC odor discrimination threshold based on divergence in PBR residues, providing a more logical pattern of MHC-based odor discrimination than found in previous training studies, where discrimination ability was not correlated with PBR divergence; and (ii) additional (non-MHC) mutations that influence odor have accumulated in these strains during the 100 generations of divergence between pure B6 and bm1 strains.     

A multiresponse parathyroid hormone assay: an inhibitor has agonist properties in vivo

Vitamin D-deficient rats subjected to thyroparathyroidectomy (TPTX) were used to evaluate in vivo the biological properties of native bovine parathyroid hormone (bPTH) and chemically synthesized fragments and analogues of the hormone on several parameters of hormone action: calcium and phosphorus fluxes, generation of cyclic adenosine 3',5'-monophosphate (cAMP), and the metabolism of 25-hydroxyvitamin D3 [25(OH)D3]. Vitamin D-deficient rats, after TPTX or sham operation, were intravenously infused with a nutrient containing 7.5 mM CaCl2 for 30 h. During the last 7 h, PTH or one of its analogues was infused intravenously at rates between 0.04 and 20 nmol/h. One hour after the start of the peptide infusion, tritiated 25(OH)D3 was injected. Urine was collected hourly for phosphate and cAMP determinations and, at the end of the experiment, blood was obtained to determine the relative accumulation of tritiated 1,25-dihydroxyvitamin D3 ([3H]1,25(OH)2D3). Infusion of bPTH-(1--84), bPTH-(1--34), human (h)PTH-(1--34), or [Nle8, Nle18, Tyr34]bPTH-(1--34) amide was accompanied by a comparable dose-dependent decrease in plasma phosphate and a dose-dependent increase in plasma calcium and [3H]-1,25(OH)2D3, and urinary excretion of phosphate and cAMP. An evaluation of [Nle8, Nle18, Tyr34]bPTH-(3--34) amide, a potent inhibitor of PTH action in vitro in the renal adenylate cyclase assay, revealed that the analogue possessed weak agonist properties in vivo. The analogue increased excretion of both cAMP and phosphate in the urine, decreased plasma phosphate levels, and increased the accumulation of [3H]-1,25(OH)2D3 in the plasma. This multiparameter model system should aid in the elucidation of the in vivo biological effects of PTH and its analogues.     

Tracing of projection neurons from the cervical dorsal horn to the medulla with the anterograde tracer biotinylated dextran amine

In addition to the well-defined role of dorsal horn neurons in pain transmission, neurons in the superficial laminae also provide a rich source of synaptic input to cardiovascular and respiratory centers in the medullary reticular formation. In this study, ascending projection neurons from the superficial laminae of the cervical enlargement were studied in the rat using the anterograde tracer biotinylated dextran amine (BDA). Ipsilateral microinjection of BDA into the cervical spinal cord (C6-C8) resulted in extensive labeling of dorsal horn neurons in laminae I-V. Axons and terminal processes of cervical dorsal horn cells projecting to the medulla were present in the cuneate nucleus (Cu), the nucleus of the solitary tract (NTS), the lateral reticular nucleus, (LRt) as well as the caudal and rostral ventrolateral medulla (VLM). The highest density of BDA labeling was found ipsilaterally in the Cu, LRt, caudal and rostral VLM, while a moderate density of labeling was present in the NTS caudal to the area postrema (AP). Moderate-to-weak labeling was also found in the LRt, the caudal and rostral VLM contralateral to the BDA injection. These results support the existence of a spinomedullary pathway that transmits noxious and innocuous Adelta and C fiber-mediated sensory signals to the medulla. Neurons in this ascending spinal pathway likely participate in the patterning of autonomic responses evoked by pain or during exercise.     

Clearance of atrial natriuretic factor by lung, liver, and kidney in human subjects and the dog.

We determined human and canine plasma clearance of atrial natriuretic factor (ANF) by lung, liver, and kidney from arteriovenous differences in plasma ANF and measured organ plasma flow. Human subjects had lower plasma ANF concentrations in the pulmonary vein or the pulmonary capillary wedge position when compared with the pulmonary artery, and both sites yielded pulmonary ANF extraction ratios of 24%. Canine lung ANF extraction was 19 +/- 3% and pulmonary ANF clearance was 328 +/- 78 ml/min per m2 vs. 357 +/- 53 ml/min per m2 in man. Hepatic plasma ANF clearance was 216 +/- 26 ml/min with an extraction ratio of 30 +/- 3% in humans and 199 +/- 89 ml/min and 36 +/- 6% in the dog. Renal plasma ANF clearance in human subjects was 78 +/- 12 ml/min per kidney and correlated well with each kidney's creatinine clearance (r = 0.58, P less than 0.05). The mean renal ANF extraction ratio was 35 +/- 4% in human subjects and 42 +/- 6% in the dog. These data quantitate the specific organ ANF clearances by lung, liver, and kidney in human subjects and in dogs and provide a rationale for elevated plasma ANF levels in cirrhosis, renal failure, and diseases accompanied by reduced perfusion of these organs. These findings support the conclusion that plasma ANF concentrations are dependent upon both the stimuli for ANF secretion as well as the specific organ clearances of ANF.     

Cognitive-behavioral therapy for persistent pain: Does adherence after treatment affect outcome?

It is a tenet of cognitive behavioral treatment of persistent pain problems that ex‐patients should adhere to treatment methods over the longer term, in order to maintain and to extend treatment gains. However, no research has quantified the causal influence of adherence on short‐term outcome in this field. The aims of this study are to assess determinants of adherence to treatment recommendations in several domains, and to examine the extent to which cognitive and behavioral adherence predicts better outcome of cognitive behavioral treatment for persistent pain. Longitudinal data from a sample of 2345 persistent pain patients who attended a multicomponent treatment programme were subjected to structural equation modeling. Adherence emerged as a mediating factor linking post‐treatment and follow‐up treatment outcome, but contributed only 3% unique variance to follow‐up outcomes. Combined end‐of‐treatment outcomes and adherence factors accounted for 72% of the variance in outcome at one‐month follow‐up. Notwithstanding shortcomings in the measurement of adherence, these findings question the emphasis normally given to adherence in the maintenance of behavioral and cognitive change, and clinical implications are discussed.