A rat model of monitoring liver allograft rejection

Rat models are often used to study liver allograft rejection. We have established a model for rat liver allograft rejection, monitored by fine needle aspiration biopsy (FNAB), in the strain combination PVG-to-BN with a mean survival time of 37 ± 20 days. In this model, we observed acute rejection with an intense peak of lymphoid blasts and lymphocyte-dominated inflammation in the FNAB [9.1 ± 3.0 corrected increment units (CIU)], and an eventual increase in macrophages (up to 4.2 ± 4.4 CIU), together with fibrosis and parenchymal necrosis in the graft. Markers of immune activation, such as an increase in IL-2-receptor (from 1 % ± 2 % to 21 % ± 13 %) and class II (from 20 % ± 9 % to 43 % ± 13 %) expressing lymphoid cells and induction of ICAM-1 in the graft, were consistent with the overall cellular response. The FNAB correlated well with parallel graft histology. In this rat model, the atraumatic monitoring makes a close follow-up possible without having to sacrifice the experimental animals. This saves work, animals, and costs in the study of liver rejection. Received: 2 July 1996 Accepted: 28 October 1996     

Preconditions for and consequences of self-determination: the psychiatric patient's point of view

In the context of an interview study concerned with self-determination in psychiatric patients, this paper describes the preconditions for and consequences of self-determination from the point of view of psychiatric patients themselves. The data were collected in semi-structured interviews with long-term psychiatric patients ( n =72) and analysed using the method of content analysis. Responses on the preconditions for self-determination were grouped into three categories: firstly, there were those who said that reference to self-determination in the case of psychiatric patients is nonsense; secondly, there were those who said that self-determination requires no preconditions; and thirdly, there were those who said that there are certain preconditions, such as the ability to think and make decisions, activity, obedience, and illness. Both positive and negative consequences were identified in situations where self-determination is maintained, but only negative consequences in situations where self-determination is lost. On the basis of these tentative results, self-determination seemed to be relevant in psychiatric nursing. We are continuing to develop and test an instrument for the evaluation of the opportunity for self-determination in clinical practice.     

Pharmacokinetics and haemodynamic effects of ISDN following different dosage forms and routes of administration

The pharmacokinetics and haemodynamic effects of isosorbide dinitrate (ISDN) have been investigated following administration of single doses as a sublingual (SL) spray (2.5 mg), sublingual tablet (5 mg) and peroral tablet (10 mg) in a randomised, placebo-controlled double-blind cross-over trial in 16 healthy volunteers.After the sublingual spray C_max was higher (39.0 ng·ml^-1) and t_max was shorter (3.9 min) than after the sublingual (22.8 ng·ml^-1 and 13.8 min) and peroral (16.9 ng·ml^-1 and 25.6 min) tablets. The AUC of ISDN did not differ following any of the three formulations (1031; 879; 997 ng·ml^-1·min, for the spray, SL tablet and PO-tablet, respectively). Mononitrate metabolites of ISDN (IS-2-MN and IS-5-MN) and total nitrates in plasma increased in proportion to the administered dose. This indicates that the fraction of the dose absorbed was the same for all the formulations but that the extent of first-pass metabolism increased in the order sublingual spray < sublingual tablet < peroral tablet. Thus, compared to the spray, the relative bioavailability of ISDN was 48% and 28% from the sublingual and peroral tablets, respectively.The haemodynamic effects were quantified using the a/b ratio of the finger pulse wave and the systolic blood pressure and heart rate under orthostatic conditions. For the a/b ratio of the finger pulse, the maximal effect was higher (e_max=130%) and the time to e_max (t_emax) shorter (16.6 min) after the spray than the sublingual tablet (84.4% and 25.5 min) or peroral tablet (90.2 and 31.3 min). The onset of effect was within 3, 5 and 7.5 min after the spray, sublingual and peroral tablets, respectively. A larger change in the orthostatically-induced decrease in systolic blood pressure and increase in heart rate was obtained following peroral than sublingual administration despite the similar plasma concentrations of ISDN. This probably reflects the larger amount of pharmacodynamically active mononitrate metabolites formed after oral dosing. The integrated effect following administration of 2.5 mg ISDN as spray was similar to that of a sublingual tablet of 5 mg.     

Flumazenil exerts intrinsic activity on sleep EEG and nocturnal hormone secretion in normal controls

The physiological function of benzodiazepine (BDZ) receptors includes regulation of sleep and neuroendocrine activity. Most of the pharmacological effects of BDZ are blocked by flumazenil. However, recent neurological and behavioral studies suggest that flumazenil has its own central intrinsic activity. This issue was addressed in a study of the sleep EEG and the nocturnal secretion of growth hormone and cortisol in ten normal male controls, who were given flumazenil either alone or in combination with the BDZ agonist midazolam, placebo and midazolam alone. Flumazenil prompted an increase in sleep onset latency, a decrease in slow wave sleep and an increase in wakefulness. Plasma cortisol concentrations after flumazenil administration were lower than after midazolam. Both flumazenil and midazolam decreased nocturnal growth hormone secretion. After simultaneous application of both BDZ receptor ligands the growth hormone blunting was amplified. Our study demonstrates that at the level of the sleep EEG and neuroendocrine activity flumazenil is capable of exerting both agonistic and inverse agonistic or antagonistic effects.Parts of this study were presented at the 69th Meeting of the Deutsche Physiologische Gesellschaft, Freiburg, 6–8 March, 1991     

Peritoneal morphology in children treated by continuous ambulatory peritoneal dialysis

Fifty peritoneal biopsies (PB) from 35 patients with end-stage renal disease, treated by continuous ambulatory peritoneal dialysis (CAPD) and aged 2 months to 18 years, were examined by light microscopy (n=50) and/or scanning electron microscopy. PB were performed during surgical procedures immediately before the start of, during, or after the cessation of CAPD treatment. PB from 15 children without renal disease undergoing laparatomy were examined similarly. Before the start of CAPD, a scarcity and shortening of the mesothelial microvilli was observed by scanning electron microscopy. During and after CAPD, variable alterations of mesothelium, interstitium and capillaries were found. The mesothelial layer was absent in all 5 PB obtained during episodes of active peritonitis. In patients treated by CAPD for longer than 6 months, mesothelial denudation was observed more frequently (6/11) than in children treated for shorter periods (1/7) (P<0.08). Fibrosis of the peritoneal membrane was present in about 50% of patients during or after the cessation of CAPD without impairment of peritoneal function. No correlation was found between the presence of fibrosis and the frequency of peritonitis or the duration of CAPD treatment.     

Utilisation des implants biodégradables dans le traitement chirurgical des fractures et au cours des ostéotomies

Résumé L'utilisation de matériaux d'ostéosynthèse biodégradables a l'avantage d'éviter la réintervention pour extraire le matériel. Les biomatériaux de polymères polyglycolides ont été expérimentés sur plus de 3 600 animaux de laboratoire avant leur introduction en pratique clinique. Depuis 1984 nous les avons utilisés comme matériau d'ostéosynthèse dans près de 1 700 cas parmi lesquels 880 cas de fracture malléolaire, 226 cas d'ostéotomie en chevron pour hallux valgus, 65 cas de fracture de la tête radiale et 54 cas de fracture de l'olécrane. Parmi les 800 premiers cas traités par broches biodégradables nous avons obtenu des résultats favorables et sans incidents dans 91 pour cent des cas. Il y eut 7 cas de fixation défaillante nécessitant une réintervention. Il y a eu 7 cas d'infection superficielle et 3 cas d'infection profonde. Nous avons observé la formation d'une collection séreuse sous-cutanée sans influence sur le résultat radiologique ou clinique dans 52 cas (6,5 %). Au vue de ces résultats et compte tenu des avantages économiques et psychologiques des matériaux biodégradables (pas de réintervention), on peut penser que l'usage de biomatériaux rivalise favorablement avec l'usage de matériaux conventionnels dans certains types d'ostéosynthèse.

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Utilization of biodegradable implants in the surgical treatment of fractures and osteotomies

Summary The utilization of biodegradable implants instead of metals in orthopaedic surgery abolishes the need to remove the fixation material. For this study biodegradable rods and screws of self-reinforced polyglycolide, polylactide and lactide-glycolide copolymer were developed and manufactured. The clinical introduction of these implants was preceded by thorough experimental studies with 3 600 animals. From November 1984 the developed biodegradable method of osteofixation was used in 1 700 operations. These included 880 displaced malleolar fractures, 226 chevron-osteotomy for hallux valgus, 65 displaced fracture of the radial head, 54 displaced frature of the olecranon and other fresh fractures or orthopaedic operations. In the first 800 cases operated on using self-reinforced polyglycolide rods the postoperative course was uneventful (91%). Because of failure in the fixation reoperation was needed in 7 cases. A superficial wound infection was observed in 7 cases, deep infection in 3 and transient fluid accumulation in 52 cases (6,5%). Fluid accumulation did not influence the radiological or clinical end-result. The advantages of biodegradable fixation are many-sided. There is a costbenefit and clinical capacity is free for other use, and psychological advantages must be emphasised because removal of implants is not needed. The over all results of this study were considered favourable.

     

Effects of ethanol on the kinetics of methyl ethyl ketone in man

The kinetics of inhaled methyl ethyl ketone (MEK) at a concentration of 200 ppm for four hours were studied in volunteers after swallowing ethanol at a dose of 0.8 g/kg. Ethanol was given either before or at the end of the exposure to MEK. The blood concentrations of MEK, 2-butanol, and 2,3-butanediol were monitored during and after the exposure. MEK concentrations in exhaled air and MEK and 2,3-butanediol concentrations in urine were also measured. Ethanol inhibited the primary oxidative metabolism of MEK and caused an increase in the blood concentrations of MEK and 2-butanol after ingestion. Ethanol ingestion, through higher blood MEK concentrations, also increased the elimination of MEK in the urine and exhaled air. Ethanol taken before exposure to MEK reduced the serum concentration of 2,3-butanediol initially but there was an increase about eight hours after the exposure. Urinary excretion of 2,3-butanediol followed the same pattern. Prior ingestion of ethanol thus seemed to interfere with the metabolism of 2,3-butanediol during and after exposure to MEK.