Indium-111-labeled platelets in monitoring human pancreatic transplants

We have performed 59 111In-labeled platelet scintigraphies in 12 patients with pancreas transplant, and we have compared retrospectively the 111In platelet uptake with the graft immunological situation. A diffuse uptake in the graft was seen in five of six patients with pancreatic rejection. The scans became positive before changes in biochemical tests were detected. No 111In platelet uptake was seen in five of seven normally functioning grafts. Two cases of venous thrombosis and two perigraft hematomas appeared like a focal 111In platelet accumulation. Indium-111-labeled platelet scintigraphy can be a useful method for monitoring pancreas transplants. It may be helpful in the early detection of pancreatic allograft rejection and in the differential diagnosis between this and other complications such as thrombosis or hematomas.     

Effect of stiripentol on carbamazepine plasma concentration and metabolism in epileptic children

Objective: To study the relationship between the plasma concentration of stiripentol (STP), a new antiepileptic drug, and its inhibitory effect on the formation of carbamazepine epoxide (CBZE) in epileptic children treated with carbamazepine (CBZ) either alone or in combination with another antiepileptic drug. Methods: Minimum plasma concentration of antiepileptic drugs was measured before initiation of STP therapy (day 0) and on days 28 (STP 60 mg⋅kg⁻¹⋅day⁻¹) and 84 (STP 90 mg⋅kg⁻¹⋅day⁻¹) by HPLC. Results: The CBZE/CBZ plasma concentration ratio decreased exponentially with increasing minimum plasma STP concentration (r = 0.80). The asymptote of the curve allowed the calculation of the minimum plasma STP concentration required to obtain the maximum inhibitory effect, i.e. 6.7 mg⋅l⁻¹. Conclusion: The inhibitory effect of STP on CBZ metabolism expressed as the CBZE/CBZ plasma concentration ratio is dependent on STP plasma concentration, with a maximum effect at an average of 7 mg⋅l⁻¹. The present data suggest that in order to evaluate the anticonvulsant efficacy of STP as add-on therapy, the minimum plasma STP concentration should be maintained above 7 mg⋅l⁻¹ and the dosage of CBZ should simultaneously be decreased in steps by more than 50% to minimize the change in CBZ plasma concentration. Received: 27 September 1995 / Accepted in revised form: 5 January 1996     

Estradiol Modulates Insulin-Like Growth Factor I Receptors and Binding Proteins in Neurons from the Hypothalamus

Trophic effects of 17β-estradiol (βE²) on in vitro developing hypothalamic cells have been reported. Insulin-like growth factor I (IGF-I) is also a potent trophic factor for cultured hypothalamic cells. An interaction between sexual steroids and insulin-like growth factors (IGFs) in modulating growth of hypothalamic cells has been suggested. Thus, we tested whether βE² modulates the levels of IGF-I, its membrane receptor and its binding proteins in rat hypothalamic culturs. Using both neuron- and glial-enriched cultures obtained from fetal rat hypothalami we found that addition of βE² elicited a significant increase in IGF-I receptor levels in neurons, without affecting its affinity. On the other hand, the three different IGF-binding proteins (IGFBPs) found in the conditioned medium of the cultures were differentially modulated by βE² in the two types of cells studied. Overall, neuronal cultures produced greater amounts of IGFBPs after treatment with βE², with IGFBP2 reaching significantly higher levels. On the contrary, treatment with βE² did not significantly alter the amounts of IGFBPs produced by glial cells. Finally, the levels of immunoreactive IGF-I found either in the medium or in cellular extracts in both neuronal and glial cultures were not modified by treatment with βE². These results strongly support previous observations of a trophic synergistic interaction between IGFs and βE² on hypothalamic cells. Thus, an increase in IGF-I receptors and/or IGFBPs after exposure to βE² may result in an enhanced response of hypothalamic neurons to IGF-I. Further, the present findings strengthen our recent observation that the effects of βE² on hypothalamic glial cells are neuronally mediated, since IGF-I receptors and IGFBPs are modulated by this sex hormone in neurons, but not in glial cells.     

An approach for dose finding of drugs in infants: sedation by midazolam studied using the continual reassessment method

Aims No drug has been demonstrated to provide simultaneously appropriate sedation, safety and lack of disturbance of the measured parameters during cardiac catheterization in infants. The objective of this study was to estimate the dose of midazolam, administered rectally, that would provide a 90% probability of adequate sedation in infants during cardiac catheterization. A sedation score ≥4 (six-point scale) 30 to 60  min after dosing was rated as a success.
Methods A double-blind, continual reassessment method using a Bayesian approach has been used. Sixteen infants were administered a single midazolam dose, within a 0.1 to 0.6  mg  kg⁻¹ dose range.
Results Consecutive failures led to allocation of the highest dose to 15 out of 16 patients. The final estimated probability of failure of the 0.6  mg  kg⁻¹ dose was 81% (95% CI: 78.5 to 84%). The time to reach a score ≥4 was longer than expected and the median duration-time at score ≥4 was shorter (15  min) than expected.
Conclusions Delayed absorption and low rectal bioavailability may explain these data. Higher doses or different routes of administration may lead to the expected sedation, but the safety of doses higher than 0.6  mg  kg⁻¹ administered rectally has not been evaluated. The therapeutic strategy for sedation of this category of infants in the hospital has now been changed based on the present results in that rectal midazolam has been abandoned in this indication.     

Vascular thymus transplantation in rats. Technique, morphology, and function

A new method of thymus transplantation is introduced, in which the graft is directly connected with the recipient's vascular system. This procedure was used both in euthymic rats and congenitally athymic nude rats. At all tested intervals after transplantation thymus grafts hardly differed from the recipient's own thymus in immunohistology and lymphocyte yield. In athymic nude rats, T cell-dependent immunity, tested by mitogen- and alloantigen-induced T cell responses, as well as by antibody production and delayed-type hypersensitivity after ovalbumin administration, showed that vascular thymus grafts could generate T cell functions to euthymic control levels. We conclude that the technique of vascular thymus transplantation represents a valuable tool, either in fundamental research on thymus function, or for the purpose of immune (re)constitution.     

Blunted gamma delta T-lymphocyte response in chronic obstructive pulmonary disease.

Chronic obstructive pulmonary disease (COPD) is characterised by an excessive inflammatory response to inhaled particles, mostly tobacco smoking. Although inflammation is present in all smokers, only a percentage of them develop COPD. T-lymphocytes are important effector and regulatory cells that participate actively in the inflammatory response of COPD. They comprise the T-cell receptor (TCR)-alpha beta (CD4+ and CD8+) and TCR-gamma delta T-lymphocytes. The latter represent a small percentage of the total T-cell population, but play a key role in tissue repair and mucosal homeostasis. To investigate TCR-alpha beta (CD4+ and CD8+) and TCR-gamma delta T-lymphocytes in COPD, the present authors determined, by flow cytometry, the distribution of both subpopulations in peripheral blood and bronchoalveolar lavage (BAL) samples obtained from patients with COPD, smokers with normal lung function and never-smokers. The present study found that: 1) the distribution of CD4+ and CD8+ lymphocytes in blood and BAL was similar in all three groups; 2) compared with nonsmokers, gamma delta T-lymphocytes were significantly increased in smokers with preserved lung function; and 3) this response was blunted in patients with COPD. These results highlight a novel, potentially relevant, pathogenic mechanism in chronic obstructive pulmonary disease.     

Lesion-induced plasticity in the second somatosensory cortex of adult macaques.

We have reported that elimination of the representation of any body part in the primary (i.e., postcentral) somatosensory cortex of the adult macaque selectively eliminates the representation of that same body part in the second somatosensory area SII. We now report that, although removal of the entire postcentral hand representation does indeed leave the SII hand representation unresponsive to somatic stimulation initially, 6-8 weeks later this cortex is no longer silent. Instead, most or all of the region that had been vacated by the hand representation is now found to be occupied by an expanded foot representation. This massive somatotopic reorganization, involving more than half the areal extent of SII, exceeds that previously observed in the postcentral cortex after peripheral nerve damage and may reflect a greater capacity for reorganizational changes in higher order than in primary sensory cortical areas.     

The major histocompatibility complex and the chemosensory recognition of individuality in rats

The present experiments provide the first evidence that congenic strains of rats, which differ only in the MHC, produce discriminably different urinary chemosignals. Urine from adult male PVG and PVG.R1 rats, which differ only in the A region (class 1) of the MHC, was used in a habituation-dishabituation task, with male PVG-RTlu, Wistar albino, and Lister hooded rats as subjects. Urine from PVG males was easily distinguished from that of PVG.R1 males by all three strains. Individual PVG males were not distinguished by their urine odours, but individual PVG.R1 males appeared to have discriminably different odours. A repetition of this experiment indicated that this discrimination may have been due to impurities in the urine. Odours from serum were not sufficient for discrimination between the two strains, nor was the class 1 molecule purified from the urine. Urine with the class 1 molecule removed (remainder fraction) could, however, be used to distinguish between the strains. The chemicals in the urine which give this distinctive odour may be fragments of the class 1 molecule or small molecules associated with the class 1 molecule. The MHC appears to control the odour cues which are used by mammals for individual recognition and may provide an olfactory basis for kin recognition but the mechanism by which the MHC controls these olfactory signals is unknown.