Renal allograft immunosuppression

We have investigated the impact of triple drug immunosuppression on the occurrence of early inflammatory episodes, as detected by fine needle aspiration biopsy, and of episodes of clinical rejection during the immediate postoperative period. The prospective component of this study includes 128 consecutive first cadaveric renal transplant recipients receiving triple drug treatment consisting of azathioprine (Aza), cyclosporin (CyA) and methylprednisolone (MP). For controls we have used three historical groups: one immunosuppressed with Aza and MP (group A), another with CyA monotherapy (group B), and the third with CyA together with MP (group C) in equivalent drug dosages. On the average, 0.8 episodes of inflammation per patient were recorded during the immediate postoperative period of 30 days with triple drug treatment. This was significantly less than the 1.3 episodes in patients receiving Aza and MP (P<0.01), the 1.7 episodes in patients on CyA monotherapy (P<0.001), or the 1.6 episodes in patients receiving CyA together with MP (P<0.001). Although the first episode of inflammation commenced concurrently in each group and the peak intensity of inflammation was the same, the mean duration of inflammation was significantly shorter-2.7 days-under triple drug treatment than the 7.8–11.7 days for controls (P<0.001). The frequency of rejection episodes under triple treatment was also significantly lower-0.2 per patient-than the 0.8 per patient in controls (P<0.001). The first rejection episode occurred later in the triple drug treatment group-on the average, on day 15.2-than in the historical controls (on days 7.7–11.7). There was, however, no difference in the duration of rejection. There were no differences in patient survival between the four groups. Graft survival was 97% at 10 weeks for triple drug-treated recipients and 79%, 68%, and 87% for first grafts in groups A, B, and C, respectively. Disregarding a minor demographic bias for the triple drugtreated group with respect to preformed antibodies and preoperative dialysis treatment, the study suggests that the triple drug protocol, in the short run, is superior to any conceivable double drug combination or CyA monotherapy.     

2,5-Hexanedione excretion after occupational exposure to n-hexane.

The urinary excretion of the n-hexane metabolite 2,5-hexanedione (HD) was determined in four shoe factory workers during four workingdays that were preceded by four free days and followed by two free days. The correlation between excretion of HD and the n-hexane concentrations in the workroom air was evaluated. The air concentrations of n-hexane and those of acetone, toluene, and other organic solvents were monitored with charcoal tubes. All the urine from each worker was collected at freely chosen intervals during the experimental period and the following two free days. The samples were analysed by gas chromatography. The relative excretion of HD increased as the exposure to n-hexane increased, although it seemed that HD accumulated progressively in the body at the highest n-hexane concentrations and at higher total solvent concentrations.     

Renal allograft immunosuppression: II. A randomized trial of withdrawal of one drug in triple drug immunosuppression

Abstract. A prospective randomized study was conducted to evaluate the impact of four different conversion protocols on graft outcome in long-term follow-up. Between January 1986 and May 1987, 128 patients with first cadaveric kidney allografts were randomized at the time of transplantation to four treatment groups of 32 patients each, to be assigned 10 weeks post-transplantation. During the first 10 weeks, all patients received triple therapy with low-dose azathioprine (Aza), cyclosporin (CyA), and methylprednisolone (MP). After 10 weeks, one group continued with triple therapy (group A) while the three other groups received different combinations of two drugs, namely, Aza and CyA (group B), Aza and MP (group C), or CyA and MP (group D). Withdrawal of MP (group B) or especially of CyA (group C) was associated with 4/29 (14%) and 10/28 (36%) acute rejection episodes, respectively, for 60 days after conversion. All rejections were mild and reversible. There were no rejections after Aza withdrawal or in the group that continued on triple therapy during the corresponding time period. The most common reason for dropping out after withdrawal, for those patients who could not continue on the originally randomized medication, was azathioprine intolerance (n= 12). Five patients were switched back to triple therapy after CyA withdrawal due to rejection. Steroid intolerance was rare and CyA in low doses was very well tolerated. At 1 year there were no statistically significant differences in graft survival between groups A, B, C, and D-81 %, 88%, 88%, and 88%, respectively-or in patient survival-88%, 88%, 88%, and 97%, respectively. For those patients continuing with the originally randomized treatment protocol, there were no differences in patient or graft survival either, the means being 91% and 89%, respectively. The most common cause of death after withdrawal was cardiovascular in nature, and there were no more fatal infections under triple drug treatment than with double drug regimens. There were no statistically significant differences in mean serum creatinine values at 1 year. The median serum creatinine values for groups A, B, C, and D were 112, 132, 133, and 133 μmol/l, respectively. At 1 year the mean CyA dose in the groups that continued with CyA was 3. 5–4. 2 mg/kg per day and CyA concentrations were equal.     

Renal transplantations from the same kidney donor: outcome of diabetic and non-diabetic patients.

Diabetic (DM) nephropathy is an indication of renal transplantation in 30% of all cases in our hospital. We assessed retrospectively the outcome of these diabetics (DM) in comparison with their non-diabetic (NDM) controls. Each diabetic (n = 24) had a control (n = 24) receiving a kidney from the same donor. There was no difference in the stage of uraemia preoperatively. Anaesthesia and fluid therapy were standardized. Peroperative hypotension occurred more often in diabetics (NS). All operating parameters including cold ischaemia were comparable. Kidney function started immediately in 14/24 in the DM group and 13/24 in the NDM group and was delayed in 10/24 and 11/24, respectively. One diabetic patient rejected the transplant as did two non-diabetic patients. Postoperatively diuretics could be discontinued more often in the DM than in the NDM group (p < 0.05). Antihypertensives had to be started in the NDM more often (NS) than in the DM group. In conclusion, the outcome of diabetic patients after renal transplantation was comparable to their NDM controls.     

High-efficiency gene transfer to primary T lymphocytes by recombinant adenovirus vectors

Recombinant, replication-deficient adenoviruses are efficient vectors for gene transfer to a wide range of cell types, with the exception of T lymphocytes. Here, we show that primary T lymphocytes from peripheral blood, cord blood, and the Jurkat T cell line are efficiently transduced by recombinant adenovirus. Nearly 100% infection efficiency of primary T cells is obtained with high multiplicity of infection (MOI) (5000) of recombinant adenovirus coding for lacZ. Similar infection efficiency by adenovirus-mediated gene transfer was obtained at lower MOI (3000) by activating primary T cells with PHA and PMA. Addition of cationic liposomes together with RAdlacZ markedly enhanced the infection efficiency at lower MOI (1000) resulting in over 90% infection efficiency. Primary T cells express low levels of coxsackievirus and adenovirus receptor (CAR), a cell surface receptor for adenovirus fiber attachment, as well as _vβ₃ and _vβ₅ integrins, cellular receptors for adenovirus internalization. This suggests that adenovirus entry to T cells at high MOI is mediated by other mechanisms. In conclusion, these results demonstrate that genes can be efficiently transferred to primary lymphocytes by adenovirus vectors at high MOI or in combination with cationic liposomes.     

Distribution of histamine in the developing peripheral nervous system

The presence and ontogenetic distribution of histamine was studied in the developing peripheral nervous system of the rat by using an indirect immunofluorescence technique and a specific rabbit anti-histamine antiserum. Histamine immunoreactivity (IR) first appeared in peripheral nerves on embryonic day 14. The number and intensity of histamine-immunoreactive nerves was highest on embryonic days 16–18. During development starting from embryonic day 14, motoneurones in ventral horns of the spinal cord at cervical, thoracic and lumbar levels contained histamine IR. A subpopulation of sensory neurones in dorsal root ganglia exhibited histamine IR. Histamine IR was also present in nerve fibres of ventral and dorsal roots of spinal cord, as well as in spinal nerves. Population of neurones and nerve fibres in sympathetic and pelvic ganglia as well as in myenteric ganglia of the intestine were also labelled with the histamine antiserum. In peripheral target organs, histamine IR was observed in nerve fibres around bronchi of the lungs, in the atria of the heart, in the adrenal gland, in the intestinal wall, in muscular tissues and in subepithelial tissue of the skin.The results of this study indicate that histamine is widely distributed in different types of neurones and nerve fibres of the developing peripheral nervous system.     

Autoimmune polyendocrinopathy – candidosis – ectodermal dystrophy (APECED): autosomal recessive inheritance

A genetic analysis was made of 58 patients and their 42 families with APECED (autoimmune polyendocrinopathy--candidosis--ectodermal dystrophy). APECED is characterized by hypoparathyroidism, primary adrenocortical failure and chronic mucocutaneous candidosis, but none of its components is constant. Other endocrine deficiencies can occur as well and also dystrophy of dental enamel and nails. The proportion of affected siblings was 0.147 +/- 0.034 (S.D.) when corrected for truncate single ascertainment, 0.246 +/- 0.019 when corrected for a priori truncate complete ascertainment and 0.240 +/- 0.047 when corrected for a posteriori truncate complete ascertainment. The male/female ratio was 1.04. The results are compatible with autosomal recessive transmission. No heterozygous manifestations of the gene were found. The gene is enriched in isolated subpopulations in central and eastern Finland. APECED is part of the "Finnish heritage of disease".