Tacrolimus inhibits platelet-derived growth factor ligand and receptor induction as well as rejection changes in rat renal allografts during long-term follow-up.
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Animals↗
Biomedical subjects
E Taskinen
Publications and source records attributed to E Taskinen.
Fine-needle aspiration biopsy allows early detection of acute rejection in children after renal transplantation.
UNLABELLED: analysis detected rejections often before clinical signs. Half of the patients had increased serum creatinine concentration and 38% had fever at the time of rejection diagnosis. Both signs were present in only 19% of the episodes. A decrease in urine output (>20%) was seen in a third of the episodes. The rejections responded well to oral methylprednisolone (3 mg/kg/day), and lymphoglobulins were needed in only 12% of the episodes. More than 90% of the rejections were completely reversible and no transplant was lost because of acute rejection. CONCLUSION: The results indicate that FNAB is a safe and sensitive method for the diagnosis and follow-up of acute cellular rejection in pediatric recipients of different ages.
Adolescent↗
Cytological monitoring of peripheral blood, bronchoalveolar lavage fluid, and transbronchial biopsy specimens during acute rejection and cytomegalovirus infection in lung and heart--lung allograft recipients.
STUDY OBJECTIVES: Acute rejection and cytomegalovirus (CMV) infection are important complications after lung and heart--lung transplantation. We sought to investigate whether acute rejection and CMV infection demonstrated as CMV antigenemia had an effect on the cell profiles of peripheral blood (PB), bronchoalveolar lavage fluid (BAL-F), or TBB histology. PATIENTS AND DESIGN: In this prospective study, composition of cells in PB, BAL-F, and TBB samples from 20 lung or heart-lung transplantation patients were analyzed during episodes of acute rejection or CMV antigenemia. Rejection was graded according to the International Society for Heart and Lung Transplantation criteria. As controls, samples with no evidence of rejection or infection were used. To evaluate the effect of time on cellular findings, samples were divided into three groups according to time after transplantation: 1--30, 31--180, and more than 180 d after transplantation. RESULTS: Acute rejection was associated with mild blood basophilia (p<0.05; specificity 94%, sensitivity 42%). In BAL-F during rejection, the number of basophils (p<0.05), eosinophils (p<0.05), and lymphocytes (p<0.05; specificity 77%, sensitivity 64%) was increased compared to controls during the post-operative month 1. Later-occurring rejections were associated with increased amounts of neutrophils in BAL-F (p<0.05; specificity 82%, sensitivity 74%). In TBB histology, acute rejections were associated with perivascular and/or peribronchial infiltration of lymphocytes (p<0.001) and plasma cells (p<0.05) compared to controls. In our patients receiving gancyclovir prophylaxis, CMV antigenemia did not significantly alter the cell profiles in PB and BAL-F nor the inflammatory cell picture in TBB histology. CONCLUSION: TBB histology remains the 'gold standard' for diagnosing rejection in lung and heart-lung transplantation patients, as the inflammatory cell findings in TBB specimens are highly specific for rejection. The cellular changes associated with rejection, mild PB basophilia and increased proportions of lymphocytes in early- and neutrophils in later-occurring rejection, observed in BAL-F cannot be considered specific for rejection, but may warrant clinical suspicion of rejection.
Acute Disease↗
Comparison of endobronchial and transbronchial biopsies with high-resolution CT (HRCIT) in the diagnosis of sarcoidosis.
High-resolution computed tomography (HRCT) has been shown to accurately visualise parenchymal infiltrates of sarcoidosis. The aim of this study was to compare the diagnostic yield (DY) of HRCT with that of endobronchial (EBB) and transbronchial (TBB) biopsies in establishing the diagnosis of sarcoidosis. Forty-five patients referred to Helsinki University Central Hospital with a presumptive diagnosis of sarcoidosis underwent fiberoptic bronchoscopy (FOB) with bronchoalveolar lavage (BAL), EBB, TBB and HRCT. Thirty-seven of the patients were diagnosed as having sarcoidosis, 34 of whom showed a parenchymal infiltrate in HRCT. One of the three patients with no parenchymal findings, had positive findings in TBB, and all had lymphocytosis in BAL. The DY for sarcoidosis by EBB and TBB was 24.3% and 50.0%, respectively. The addition of EBB to TBB improved the DY by 8.3%, whereas adding TBB to EBB improved the DY by 30.6%. There were no major complications after the FOB, which was always performed under fluoroscopic control. In conclusion, HRCT is a valuable tool in diagnosing sarcoidosis. However, the HRCT findings cannot be seen in all patients with positive findings in lung biopsy, nor is the parenchymal infiltrate specific for sarcoidosis. Attempting biopsy-proven diagnosis of sarcoidosis is still recommended. Fiberoptic bronchoscopy with EBB and TBB under fluoroscopic control is a safe and well-tolerated procedure.
Adult↗
Factors affecting the cytology outcome of Pap smears--a brief approach to internal quality control in private cytopathology laboratory practice.
We evaluated the effect of intrauterine device (IUD), patient age and hormone replacement therapy (HRT) on cytology outcome in Pap smears together with the important IQC procedures: 1) manual double-screening by cytotechnologists, and 2) retrospective senior pathologist review during 1996-1999. The results from primary double-screening (119 of 87,409 Pap smears) showed an excellent inter-observer correlation. The estimation of hormonal effects showed higher incidence of disagreements (p=0.013) in patients <47 yr. Some individual trends were found in the assessments of both cellular atypia (p=0.012) and Papanicolaou classification (p=0.018). The IUD had no influence on the accuracy when the degree of inflammatory reaction was evaluated (p>0.050), but showed an adverse effect on the estimation of cellular atypia (p=0.001). HRT distinctly equalized the entire sample material, since fewer disagreements were found in the age groups <47 yr and >47 yr when estimating the hormonal effects (p=0.013), inflammatory reaction (p=0.044) or cellular atypia (p=0.006) compared to those without HRT. The continuous cytopathologist supervision had a positive impact on the accuracy of hormonal effect estimation during the 4 years. The senior cytopathologists' reviews (354 of 87,409 Pap smears) showed mutually good interobserver correlation, and diagnostic conclusions of the same specimens differed only slightly between the cytopathologists. We found these state-of-the-art cytopathological IQC procedures to be effective and fit-for-purpose when evaluating hormonal effects, inflammatory reaction and cellular atypia.
Adult↗
MC1288, a vitamin D analog, prevents acute graft-versus-host disease in rat bone marrow transplantation.
The major obstacle to successful bone marrow transplantation (BMT) is graft-versus-host disease (GVHD). Vitamin D analogs have shown their efficacy in solid organ transplantation. The purpose of this study was to investigate the suitability of a novel vitamin D analog, MC1288, in the prevention of acute GVHD in a rat BMT model. Allogeneic BMT were performed from Lewis to BN rats (n = 18). The animals were divided into four groups: an untreated control group, MC1288, cyclosporin A (CsA), and MC1288 + CsA-treated groups. Rats were harvested for histology and immunohistochemistry on day 20 after BMT. Histological changes for GVHD in liver, skin, and spleen were scored. Positivity in immunostaining was quantified as the number of positive cells/high power field. Treatment with MC1288 decreased clinical signs of GVHD compared with untreated or CsA-treated rats. Histological manifestations of GVHD, expressed as mean total increment, were significantly lower (1.4 +/- 0.5) in MC1288 than in untreated (5.0 +/- 1.6) or CsA (3.5 +/- 1.0) groups. Combining MC1288 and CsA further improved histology (1.1 +/- 0.6). The expression of CD4, CD8, MHC class II, interleukin-2 receptor, nitric oxide 2, and NKR-P1A (NK cells) positivity was significantly decreased in the liver and skin of BMT rats by MC1288. MC1288 was effective in preventing clinical and histological signs and symptoms of GVHD. This novel vitamin D analog could be used as an immunomodulating agent in BMT.
Acute Disease↗
Structure of carotid artery in baboon and rat and differences in their response to endothelial denudation angioplasty.
BACKGROUND: Most studies dealing with vascular response to injury have been conducted using rodent and rabbit models, although it is expected that the response to injury in these species is dissimilar from man. AIMS: Here we compare the structure of native carotid artery in rat and baboon and the response of these vessels to endothelial denudation angioplasty. METHODS: In both species, the carotid is a musculoelastic artery. Only baboon carotid has a distinct intima, correlating in size with the weight of male baboons. Complete endothelial denudation of left carotid was performed on eight male baboons and 24 male rats by applying an equivalent pull force with a Fogarthy catheter. The animals were sacrificed prior to and 15 min and 2, 3, 4, 7, 14 and 28 days postinjury, one baboon and three rats per time point. RESULTS: Re-endothelialization in the baboon was complete already on day 4, whereas in the rat it was still incomplete on day 28. The proliferative response to injury was far smaller in the baboon than in the rat, the intimal area increased only by 5-fold in baboon compared with 25-fold in rat, and the number of intimal nuclei by 4-fold in baboon compared with 12-fold in rat. Complete compensatory remodelling of the lumen size occurred in the baboon, whereas in the rat remodelling remained incomplete. The cell types participating in the response were, however, similar: deposition of thrombocytes on denuded luminal surface, expression of alpha-actin by intimal cells, and lack of any significant white cell infiltration in the denuded intima. CONCLUSIONS: Baboon carotids are very different from rat carotids both in their native structure and in their response to injury. With the limited amount of information available from human vessels, baboon carotids closely resemble human carotids in both respects.
Angioplasty, Balloon↗
Obliterative airway disease in a porcine heterotopic bronchial allograft model.
Representative animal models are needed for the study of posttransplant obliterative bronchiolitis (OB). Because human OB originates in terminal bronchi, the validity of tracheal models can be questioned. Using our hetrotopic model, we implanted pieces of a lobar bronchus subcutaneously into domestic pigs. Five groups were included: autograft implants, allograft implants, allograft implants with 2 regimens of cyclosporine (CsA)azathioprine (AZA)-methylprednisolone (MP), and allograft implants with CsA-SDZ RAD-MP. Samples were harvested at 2 weeks and at 1, 2, and 3 months. The histological findings were graded from 0 to 3. Following initial ischemic epithelial damage, autograft implants recovered, but untreated allografts and those treated with CsA-AZA-MP were totally and permanently damaged within one month. In the group treated with CsA-SDZ RAD-MP, a maximal grade 1.5 +/- 0.5 epithelial injury was seen at one month. Epithelial damage preceded and correlated with luminal obliteration. The obliterative lesions histologically resembled human OB. Differences from our previous findings with terminal bronchioles were minor. This study supports the use of larger-size airways in the study of OB.
Animals↗
Protocol core biopsy (CADI): a surrogate marker for chronic rejection. Mycophenolate Mofetil ICM 1866 and IICR 023 Study Groups.
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Biopsy↗
Healing of bronchial allografts in pigs.
Our purpose was to investigate the healing of bronchial grafts in a porcine experimental model. Via left thoracotomy, a 2.5 cm long bronchial stump was anastomosed back to the same animal (autograft) or to another pig (allograft). Autotransplanted bronchi (six pigs) healed very well without infection. Allotransplantation without immunosuppression (eight pigs) was followed in all cases by rejection with formation of major bronchopleural fistula. After allotransplantation with triple-drug immunosuppressive medication (seven pigs), three pigs showed infection-free healing, but the anastomoses were slightly stenosed at the time of sacrifice (mean 30 d), while four had bronchopleural fistula. The study thus showed the healing ability of totally avascular bronchial graft in pigs to be very good when it is autotransplanted, but poor when allotransplanted without immunosuppressive treatment.
Animals↗
Post-transplantation histology as surrogate marker for long-term kidney allograft outcome.
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Animals↗
Differentiation between vasculoprotective and uterotrophic effects of ligands with different binding affinities to estrogen receptors alpha and beta.
Estrogen-based drug therapy in cardiovascular diseases has been difficult because it has not been possible to separate the wanted vasculoprotective effect from the unwanted effects of the hormone to the reproductive system. Here, we demonstrate that, after endothelial denudation of rat carotid artery, the mRNA of the classical estrogen receptor (ERalpha) is constitutively expressed at a low level whereas the expression of the novel ERbeta mRNA increases >40-fold. Under in situ hybridization and immunohistochemistry, ERbeta mRNA and protein colocalize with the smooth muscle cells in the media and neointima. Treatment of ovariectomized female rats with the isoflavone phytoestrogen genistein, which shows 20-fold higher binding affinity to ERbeta than to ERalpha, or with 17beta-estradiol, which does not differentiate between the two receptors, provides similar dose-dependent vasculoprotective effect in rat carotid injury model. In addition in concentrations <10 microM, both ligands are equally inhibitory to the replication and migration of smooth muscle cells in vitro. However, only treatment with 17beta-estradiol, but not with genistein, is accompanied with a dose-dependent uterotrophic effect. The results suggest that preferential targeting to ERbeta will provide vasculoprotective estrogen analogs devoid of effects to the reproductive system.
Animals↗
Tumour response and radiation-induced lung injury in patients with recurrent small cell lung cancer treated with radiotherapy and concomitant interferon-alpha.
The aim of this study was to determine whether either natural or recombinant interferon (IFN)-alpha can improve the response to radiotherapy (RT) in patients with small cell lung cancer (SCLC), and to assess the role of IFN in radiation-induced lung injury. All patients had previously participated in a randomised trial of chemotherapy alone or in combination with IFN-alpha in three arms (arm O: no IFN, arm I: natural IFN-alpha, arm II: recombinant IFN-alpha). Patients with locally progressive disease in the lungs following chemotherapy were treated with RT and they continued with their concomitant IFN-alpha. The RT dose was 50 Gy. Radiation-induced lung injury was assessed by lung function tests, computed tomography and bronchoalveolar lavage fluid (BALF) analysis which included cell findings, Interleukin (IL)-1 alpha/-1 beta expression by alveolar macrophages and surfactant components. Seventeen patients were entered in the study, 16 of whom were evaluable. Response rates in Arms O, I and II were 50, 67 and 50%, respectively. Median survival was 18.5, 7 and 23 months respectively, and 1-year survival was 67, 29 and 75% respectively. Long-term survival as assessed by 2- and 3-year survival rates was 29% in patients receiving natural IFN-alpha as compared to 17% in patients not receiving IFN (not statistically significant findings). Every patient had abnormal results when assessed for radiation-induced lung injury. No statistically significant difference was found in toxicity between the treatment arms. A high surfactant protein (SP)-A/phospholipid ratio and a high level of SP-A in BALF before RT was associated with a high degree of radiation-induced lung injury measured by lung function tests and computed tomography in all arms of the study. Thus, we could not show that the combination of IFN-alpha and RT induced more lung toxicity than RT alone as we did in our previous study. The role of high SP-A/phospholipid ratios and high SP-A levels in BALF before RT as predictors of the development of lung injury after RT needs to be determined in the future.
Adult↗
Obliterative lesions in small airways in an immunosuppressed porcine heterotopic bronchial allograft model.
We have recently developed a heterotopic large-animal model for research into obliterative lesions in small airways caused by allograft rejection. In this model, the small airways of subcutaneously implanted allografts gradually obliterate, whereas autografts remain patient. Twenty lung fragments and 20 segments of bronchi were implanted in domestic pigs weighing 20 kg from non-related donors. The histology of five animals receiving daily cyclosporine A (CsA) (10 mg/kg), azathioprine (2 mg/kg) and methylprednisolone (20 mg), Group C, was compared with that of six animals without immunosuppression, Group A. Four animals received monotherapy with CsA (10 mg/kg) or methylprednisolone (3 mg/kg). The histological findings were graded from 0 to 3 on the basis of implants harvested repeatedly over 3 months. Epithelial destruction and bronchial obliteration was rapid and permanent in all the allografts. Inflammation and fibrosis of the bronchial wall was less prominent in Group C than in Group A and the onset of fibrosis was delayed. Cartilage degeneration and pericartilagineous inflammation were significantly less severe in Group C (P < 0.05). Monotherapy was less potent than triple therapy. This large-animal model is useful for studying the effects of immunosuppressive drugs on obliterative airway disease.
Animals↗
Effects of rapamycin analogue SDZ RAD on obliterative lesions in a porcine heterotopic bronchial allograft model.
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Animals↗
Raised endothelin content in bronchoalveolar lavage fluid during lung allograft rejection in pigs.
Various pathophysiologic mechanisms are implicated in the rejection of transplanted lungs, for example production of vasoactive substances such as endothelin. In this study the measured endothelin content of bronchoalveolar lavage (BAL) fluid was correlated to the grade of lung allograft rejection. Left lung allotransplantation was performed in seven piglets (weight 16-24 kg). Triple-drug immunosuppression (cyclosporin, azathioprine, methylprednisolone) was given, and episodes of acute rejection were induced by withdrawing the medication. The development of acute rejection was monitored with computed tomography and bronchoscopy with BAL and transbronchial biopsy. In 46 BAL samples the endothelin content was radioimmunologically assayed. Transbronchial biopsies taken simultaneously showed grade 0 rejection in 17 tissue samples, grade 1 in 21 and grade 2 in eight. The endothelin content of BAL (pg/ml) increased from 34.3 +/- 6.1 in grade 0 rejection to 54.6 +/- 6.8 in grade 1 and to 98.5 +/- 35.6 in grade 2. The increase from grade 0 was statistically significant to grade 1 (p < 0.05) and to grade 2 (p < 0.02). The increased endothelin content of BAL may have harmful effects on the lung, as endothelin is a potent vaso- and bronchoconstrictive peptide with mitogenic properties.
Animals↗
Human herpesvirus-6 infection after liver transplantation.
A diagnosis of posttransplantation human herpesvirus-6 (HHV-6) infection was established for eight adult recipients among a liver transplantation patient population of 121. The diagnosis was based on serology and demonstration of HHV-6 specific antigens in liver biopsy specimens with use of monoclonal antibodies and immunoperoxidase staining. A significant graft dysfunction was recorded in association with serodiagnosis. HHV-6 early antigens, as well as HHV-6 variant B antigens, were detected retrospectively in all six available liver biopsy specimens. Histologic examination of biopsy specimens demonstrated acute rejection in 5 of the 8 patients, and 3 patients had portal lymphocyte infiltration. In five cases cytomegalovirus (CMV) infection was associated with HHV-6 infection; in four cases CMV antigens were also detected in the biopsy specimens. Two patients who had pure HHV-6 infection without CMV infection or rejection had significantly impaired graft function, with a positive antigen-detection test. Thus, HHV-6 may infect the liver allograft and cause graft dysfunction and may possibly be associated with rejection and/or CMV infection.
Adult↗
Small airway obliteration in a new swine heterotopic lung and bronchial allograft model.
BACKGROUND: We studied a heterotopic large-animal model with obliterative airway lesions caused by allograft rejection. METHODS: Lung fragments (1 cm3) with airways (LB), and 1 to 2 mm diameter bronchi alone (B) were implanted subcutaneously in 11 domestic piglets weighing 20 kg. Six animals each received 40 implants from nonrelated donors without immunosuppression (group A). Another 5 animals had autograft implants (group U). The implants were harvested consecutively for histologic analysis over 3 months in group A and 6 months in group U. RESULTS: In group U, the initial ischemia caused mild to moderate epithelial damage with moderate metaplasia but with a return to normal ciliary epithelium within 1 month. Transient mild luminal obliteration with granulation tissue and mononuclear cells was observed during the first weeks, but after 4 weeks the lumen was patent and filled with mucus. In the bronchial wall, moderate fibrosis developed in LB implants, whereas mild fibrosis was seen in B implants. In group A, the epithelium was totally absent by 2 weeks, and mild inflammation, fibrosis, and destruction of the cartilage with pericartilaginous mononuclear accumulation were observed in the bronchial wall. Small airways were gradually obliterated between days 7 and 21, initially by granulation tissue and mononuclear cells and later by progressive fibrosis. CONCLUSIONS: In this model, autografted airway implants stayed patent for at least 6 months, whereas total luminal obliteration histologically resembling obliterative bronchiolitis developed in allografts within 21 days. Because small airways, including bronchioli, can be transplanted with the use of this model, it may be useful for research into the causes of airway obliteration, which may be relevant to the pathogenesis of obliterative bronchiolitis in lung recipients.
Animals↗