A REPRODUCIBLE MODEL OF CHRONIC REJECTION IN RAT RENAL ALLOGRAFTS

A reproducible animal model is essential for the study of the pathogenesis of chronic rejection. This study investigates: (i) the optimal pre-transplant blood transfusion conditions to induce tolerance in a strongly rejecting rat kidney allograft model (Dark Agouti to Albino-Surgery) and avoiding post-transplant immunosuppression; (ii) the functional and histological changes that occur in long-term surviving kidneys and their similarity to chronic rejection; and (iii) the maintenance of tolerance. Prolonged survival occurred after administration of at least two donor blood transfusions with concomitant cyclosporin A (5 mg/kg per day). The time-span between transfusions appeared to be critical: 4 days was more effective than 2 or 7 days. Ineffective treatment led to death within the first 2 weeks post-transplant with histological evidence of acute graft rejection. Seventy-five per cent of long-term survivors experienced impaired renal function in the first week which improved spontaneously and remained stable in 93% of the surviving animals after 100 days and in 668 after 200 days. The morphology of long-term allografts was extremely variable from minor to extensive tubular atrophy, interstitial fibrosis, glomerular hypertrophy, focal and segmental glomerulosclerosis and vascular changes. Glomerular hypertrophy occurred in uninephrectomized controls and probably denoted a response to uninephrectomy. Glomerulosclerosis increased with time and was absent in controls. Although chronic damage was evident, the rats remained tolerant to fresh donor skin. Replacement of the original kidney allograft with a fresh donor kidney resulted in 70% survival. These second grafts showed less severe renal dysfunction and morphological damage than the original allografts in the long-term follow up.     

The pharmacology of GR203040, a novel, potent and selective non-peptide tachykinin NK1 receptor antagonist.

1. The in vitro and in vivo pharmacology of GR203040 ((2S, 3S)-2-methoxy-5-tetrazol-1-yl-benzyl-(2-phenyl-piperidin-3-y l)-amine), a novel, highly potent and selective non-peptide tachykinin NK1 receptor antagonist, was investigated in the present study. 2. GR203040 potently inhibited [3H]-substance P binding to human NK1 receptors expressed in Chinese hamster ovary (CHO) and U373 MG astrocytoma cells, and NK1 receptors in ferret and gerbil cortex (pKi values of 10.3, 10.5, 10.1 and 10.1 respectively). GR203040 had lower affinity at rat NK1 receptors (pKi = 8.6) and little affinity for human NK2 receptors (pKi < 5.0) in CHO cells and NK3 receptors in guinea-pig cortex (pKi < 6.0). With the exception of the histamine H1 receptor (pIC50 = 7.5). GR203040 had little affinity (pIC50 < 6.0) at all non-NK1 receptors and ion channels examined. Furthermore, GR203040 produced only weak inhibition of Na+ currents in SH-SY5Y neuroblastoma and superior cervical ganglion cells (pIC50 values < 4.0). GR203040 produced only weak antagonism of Ca(2+)-evoked contractions of rat isolated portal vein (pKn = 4.1). The enantiomer of GR203040, GR205608 (2R, 3R)-2-methoxy-5-tetrazol-1-yl-benzyl-(2-phenyl-piperidin-3-y l)-amine), had 10,000 fold lower affinity at the human NK1 receptor expressed in CHO cells (pKi = 6.3). 3. In gerbil ex vivo binding experiments, GR203040 produced a dose-dependent inhibition of the binding of [3H]-substance P to cerebral cortical membranes (ED50 = 15 micrograms kg-1 s.c. and 0.42 mg kg-1 p.o.). At 10 micrograms kg-1 s.c., the inhibition of [3H]-substance P binding was maintained for > 6 h. In the rat, GR203040 was less potent (ED50 = 15.4 mg kg-1 s.c.) probably reflecting, at least in part, its lower affinity at the rat NK1 receptor. 4. In guinea-pig isolated ileum and dog isolated middle cerebral and basilar arteries, GR203040 produced a rightward displacement of the concentration-effect curves to substance P methyl ester (SPOMe) with suppression of the maximum agonist response (apparent pKB values of 11.9, 11.2 and 11.1 respectively). 5. In anaesthetized rabbits, GR203040 antagonized reductions in carotid arterial vascular resistance evoked by SPOMe, injected via the lingual artery (DR10 (i.e. the dose producing a dose-ratio of 10) = 1.1 micrograms kg-1, i.v.). At a dose 20 fold greater than its DR10 value (i.e. 22 micrograms kg-1, i.v.), significant antagonism was evident more than 2 h after GR203040 administration. 6. In anaesthetized rats, GR203040 (3 and 10 mg kg-1, i.v.) produced a dose-dependent inhibition of plasma protein extravasation in dura mater, conjunctiva, eyelid and lip in response to electrical stimulation of the trigeminal ganglion. 7. It is concluded that GR203040 is one of the most potent and selective NK1 receptor antagonists yet described, and as such, has considerable potential as a pharmacological tool to characterize the physiological and pathological roles of substance P and NK1 receptors. GR203040 may also have potential as a novel therapeutic agent for the treatment of conditions such as migraine, emesis and pain.     

Myocardial dysfunction in ankylosing spondylitis.

Echocardiographic evidence has suggested abnormalities of the myocardial function in patients with ankylosing spondylitis. In this work the cardiac function in patients with ankylosing spondylitis and in normal volunteers was evaluated. Twenty four normal volunteers and 21 patients with ankylosing spondylitis aged 18-45 were studied. None had overt cardiac disease. Cardiac function was assessed at rest with echocardiography, at rest and during supine bicycle exercise using radionuclide angiography in the left anterior oblique position following equilibration with 740 MBq of technetium-99. The subjects undertook supine bicycle exercise with 30 W increments every three minutes to the point of fatigue. Comparison of data from normal volunteers and patients with ankylosing spondylitis were made using Student's t test for independent samples or the Mann-Whitney non-parametric technique, as appropriate. Subjects were matched for age, sex, height, and weight. There were no echocardiographic differences; however, global nuclide left ventricular function showed several differences between normal volunteers and patients with ankylosing spondylitis. The peak filling rate during exercise was significantly lower in patients with ankylosing spondylitis: normal volunteers 6.5 (SD 1.2); patients with ankylosing spondylitis 5.7 (1.2). The time to reach peak filling during exercise was significantly lower in patients with ankylosing spondylitis: normal volunteers 102 (22); patients with ankylosing spondylitis 120 (23). Regional analysis also showed differences between patients with ankylosing spondylitis and normal volunteers both at rest and during exercise. In the anteroseptal region the filling fraction and peak filling rate were significantly lower in patients with ankylosing spondylitis. Most of the differences (although not all) were in the variables of diastolic function. This study shows that there are subtle abnormalities in cardiac function in patients with ankylosing spondylitis. The major abnormalities are in the diastolic function, suggesting a decrease in left ventricular compliance.     

Eye-tracking dysfunction in the affective psychoses and schizophrenia.

Smooth pursuit eye movements to a sinusoidally moving target were recorded using the electro-oculogram in 49 subjects with bipolar disorder, 19 with major depressive disorder and 61 with definite schizophrenia, and compared with 145 normal controls. The signals were analysed in the frequency domain to yield a signal to noise ratio that is known to relate to accuracy of smooth pursuit. Smooth pursuit was found to be significantly poorer in schizophrenics than in bipolars, major depressed or controls. Eye-tracking performance was independent of the effects of neuroleptics, tricyclic antidepressants or lithium, and was not altered by the severity of depression in the affective psychoses. There was a small, but significant worsening of smooth pursuit with age in controls and schizophrenics, but this did not account for the group differences. The results support the view that among the major psychoses eye-tracking dysfunction is specific to schizophrenia.     

Current clinical laboratory practice: investigation of plasma lipids--which tests and when?

Clinical interest in the lipoproteins stems mainly from the association between serum cholesterol concentrations and coronary heart disease. Investigations of lipoproteins should be performed in patients with premature coronary heart disease, with a strong family history of coronary heart disease, or with certain cutaneous stigmata of hyperlipoproteinaemia and when fasting serum samples are seen to be lipaemic. Family studies should be performed in appropriate cases to identify relatives at increased risk of developing coronary heart disease. Patients with conditions known to cause secondary hyperlipoproteinaemia should be investigated if they fall into one of these categories but only after treatment of the underlying condition. Non-specialist laboratories should be able to measure total cholesterol and triglyceride concentrations and high density lipoprotein cholesterol concentrations. Lipoprotein electrophoresis has a limited role in such laboratories and is not necessary as a routine procedure. Specialist laboratories should in addition be able to measure individual lipoproteins and identify apolipoprotein E phenotypes.     

An alternative approach to contrast-detail testing of X-ray image intensifier systems.

The difficulties of making the results of threshold contrast-detail diameter tests on X-ray image intensifier systems consistent with published performance standards are discussed. The current approach to contrast-detail testing is described and an alternative method intended to give greater consistency for all image intensifier input field diameters proposed. The current and alternative test conditions are compared on two image intensifier systems. The results obtained show that the contrast-detail curves for image intensifier systems with a wide range of input field diameters can be effectively normalized to be directly comparable to a common reference standard by applying the proposed alternative test conditions. The implications of this result on the interpretation of the contrast-detail test are discussed.     

Space time clustering of births in SIDS: do perinatal infections play a role?

The aetiology of sudden infant death syndrome (SIDS) remains uncertain; many causal pathways have been proposed. In this paper we have examined firstly the variation in the risk of SIDS with age, month of death and month of birth; and secondly the space time clustering of SIDS deaths, and, separately, space time clustering of their births. Data were obtained from the Office of Populations, Censuses and Surveys on all certified SIDS deaths in the period; children were assigned grid references for the address of birth and of death. Data on number of births were abstracted from published material. A log-linear modelling technique was used to investigate the separate effects of age, month of death and month of birth on the risk of SIDS. The Knox method was used to investigate space time clustering of deaths and of births of children who died of SIDS. Separate, statistically significant effects were found for age, month of death and month of birth. There was minor space time clustering of SIDS births and deaths at large time and space intervals, and a marked space time clustering of births in short space time intervals in the first quarter of the year. The finding of an effect of month of birth on the risk of SIDS, and of space time clustering of births suggest that a perinatal hazard--possibly of infectious origin--may play a role in the aetiology of SIDS.