Protocol core biopsy as intermediate efficacy end-point in chronic kidney allograft rejection.
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Biomedical subjects
Publications and source records attributed to E Taskinen.
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PURPOSE: A Phase I trial was conducted to investigate clinical toxicity, pharmacokinetics, and chemiluminescence (CL) responses of alveolar macrophages (AM) and peripheral blood neutrophils and monocytes after inhalation of recombinant interferon (r IFN)-gamma. METHODS AND MATERIALS: Eight patients with lung cancer inhaled r IFN-gamma as single doses of 0.1, 0.2, 0.6, 1.8, or 5.4 mg. Bronchoalveolar lavage was performed three times, 21 h before as well as 3 and 27 h after inhalation. RESULTS: Interferon-gamma was detectable in bronchoalveolar lavage fluid (BALF) samples taken 3 h after inhalation in doses of > or = 0.6 mg. Before inhalation, AM in four out of seven patients studied showed vigorous lucigenin-enhanced CL responses to N-formyl-methionyl-leucyl-phenylalanine and opsonized zymosan particles. Furthermore, the responses were markedly increased 3 h after inhalation. In three out of seven patients, AM in the pretreatment BALF samples showed low or no CL responses, and the responses did not increase after inhalation of IFN-gamma, suggesting that the patients were anergic. Postinhalation CL responses did not correlate with the dose of IFN-gamma inhaled. Circulating IFN-gamma was detected in one patient receiving the highest dose. No changes referable to IFN-gamma inhalation were found in the CL responses of blood neutrophils and monocytes. During the 24 h follow-up, two patients developed transient fever-reactions. CONCLUSIONS: The findings suggest that inhalation may provide a way to increase alveolar concentrations of IFN-gamma and to augment respiratory burst capacity of AM without any major side effects. This approach may have clinical implications for the treatment of tumors and infections of the respiratory tract.
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Chronic rejection has emerged as a major problem in renal transplantation, and clinical trials for prophylaxis and therapy are underway. Use of graft and patient survival as endpoints in prophylactic studies requires long follow-ups to read the endpoint. There is also an obvious need for a starting point for intervention studies. Previously, we formed a histological chronic allograft damage index (CADI), based on numerical scoring of histological alterations compatible with chronic rejection. Using protocol core needle biopsies of 89 functioning grafts 2 years after transplantation and a follow-up of 6 years, we demonstrate now that (a) the CADI at 2 years correlates significantly (r = 0.717, P = 0.0001) with transplant function at 6 years, and (b) that the CADI at 2 years reliably (P = 0.001) predicts the patients who will proceed to clinical chronic rejection later. As protocol core biopsy is an early predictive parameter for chronic rejection, our results suggest that a protocol core biopsy (at 2 years or possibly even earlier) should be included in all clinical investigative protocols dealing with chronic renal allograft rejection.
Concentrations of asbestos bodies (AB) were assessed by optical microscopy of 10 ml iron-stained samples and compared with the exposure history acquired by personal interview for 156 patients. Concentrations equalling or exceeding 1 AB/ml were found in 85% of patients who had been heavily exposed to asbestos and only 7% of those who were unlikely to have been exposed. Elevated AB concentrations were observed among primary asbestos, shipyard and construction workers. Smoking was not found to affect the AB concentrations. The use of Papanicolaou-stained cytological Millipore preparations during routine screening was a less sensitive method for the assessment of AB concentrations than that involving iron-stained preparations. The expression of AB concentration as AB/ml or AB/million cells were found to be equally useful indicators of exposure. The correlation between AB concentration and exposure history was greater than in earlier studies on workers exposed to chrysotile. Concentrations exceeding 1 AB/ml were indicative of a nontrivial exposure to asbestos. Despite the observed correlation between AB concentration and exposure history, the individual variability of AB counts, methodological differences and laboratory-bound reference values are important in the interpretation of AB concentrations in bronchoalveolar lavage (BAL) fluid at individual level.
We have created the chronic allograft damage index (CADI), which quantifies the early histopathological changes in renal allografts. In this study we showed that the CADI at 2 years after renal transplantation predicted the graft outcome 4 years later and that the CADI identified the risk group that proceeded to chronic rejection during subsequent years.
Twenty-six radiological, endoscopic and histological examinations of the large bowel were performed in 25 patients with ulcerative colitis. Extensive colitis was observed in 42% of the radiological, in 38% of the endoscopic, and in 27% of the histological examinations. Agreement as to the extent of the colitis between all three examination methods was reached in 53% of the cases. The endoscopic extent of colitis varied between left-sided and extensive in 41% of the patients during a 7-year median follow-up. The frequent change in the extent of ulcerative colitis and the considerable disagreement between radiography, colonoscopy and histology in evaluating the extent of colitis justify the question, "Does a true, unambiguous extent of colitis really exist?" It is more likely that the extent of colitis is just a function of time and the examination method used.
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A Phase I trial was conducted to investigate the clinical toxicity, pharmacokinetics, and chemiluminescence (CL) responses of alveolar macrophages (AMs), peripheral blood neutrophils, and monocytes after subcutaneous injection of recombinant interferon-gamma (rIFN-gamma). Six patients with lung cancer received rIFN-gamma subcutaneously as single doses of 0.2, 0.6, and 1.8 mg. Bronchoalveolar lavage was performed three times: 21 h before as well as 6-7 and 27 h after injection. Serum samples were taken five times during the 27-h follow-up. IFN concentrations were measured from alveolar epithelial lining fluid (ELF) and serum by using an antiviral bioassay. IFN-gamma was not detectable in ELF after subcutaneous injection. AMs did not effect an increase in CL responses to N-formyl-methionyl-leucyl-phenylalanine or to phosphate-buffered saline. Circulating IFN-gamma was detectable at 3-12 h after an injection of 1.8 mg of rIFN-gamma, the highest dose given. CL responses of peripheral blood monocytes increased in all patients after injection, whereas the responses of neutrophils were less clear-cut. All patients developed systemic side effects such as transient fever, nausea, headaches, and flu-like symptoms. The findings suggest that rIFN-gamma passes poorly from the blood to the pulmonary alveoli. On the basis of this and our previous findings of increased CL responses in AMs and measurable IFN concentrations in ELF after inhalation of rIFN-gamma, we recommend inhalation rather than the parenteral route of IFN-gamma for the treatment of respiratory diseases.
PURPOSE: To evaluate the diagnostic potential of bronchoalveolar lavage fluid analysis in radiation-induced lung injury. METHODS AND MATERIALS: Thirty patients with inoperable non-small cell lung cancer received either high-dose hyperfractionated radiotherapy or radiotherapy and interferon, a potential radiosensitizer, or radiotherapy and N-acetylcysteine, a potential radioprotector. Bronchoalveolar lavages were performed before and immediately after radiotherapy, and thereafter 6-8 weeks and 3 months after radiotherapy. Total and differential cell counts were measured from the bronchoalveolar lavage fluid samples. Urea measured in serum and in bronchoalveolar lavage fluid was used to calculate epithelial lining fluid. The concentrations of protein and phosphatidylcholine, the major surfactant phospholipid, in epithelial lining fluid were measured. The extent of radiation-induced lung injury was assessed from computed tomographies performed before radiotherapy, and 6-8 weeks and 3 months after radiotherapy. RESULTS: More patients in the interferon-arm developed radiation pneumonitis than did patients in the other groups, but no significant differences in alveolar fluid indices were noted between the groups. When all the patients were studied together, radiation was shown to have induced a significant relative increase of lymphocytes in bronchoalveolar lavage fluid 6-8 weeks and 3 months after the end of radiotherapy. The concentration of phosphatidylcholine in epithelial lining fluid decreased significantly 6-8 weeks and 3 months after treatment. The increase in protein concentration in epithelial lining fluid reached a statistically significant level 6-8 weeks after radiotherapy. CONCLUSION: Analysis of bronchoalveolar lavage fluid predicts the degree of radiation pneumonitis; however, radiology remains to be "the gold standard."
We analyzed the expression of class II antigens on graft tubular cells and the expression of IL-2R on lymphoid cells in 314 prospective aspiration biopsies taken from 30 consecutive patients with histologically verified acute vascular rejection (AVR). Based on histology, two main groups were seen: 11 grafts had features of AVR only and 19 grafts had a combination of AVR and acute cellular rejection (ACR). The AVR findings were also predominant in the latter group. In the grafts with a combination of AVR and ACR, patterns similar to ordinary ACR were seen in class II and IL-2R expression. On the contrary, no class II or IL-2R induction could be seen in the grafts with pure AVR and irreversible rejection. This pattern, demonstrated by immunocytology, suggested that AVR is a heterogenous group of rejections, where different cellular and molecular mechanisms are operating. Humoral mechanisms might be involved in these rejections.