Bronchoalveolar lavage in amiodarone pneumonitis. Cellular abnormalities and their relevance to pathogenesis

To investigate the contribution of direct cytotoxicity and immune-mediated hypersensitivity to the pathogenesis of amiodarone pneumonitis, we evaluated cells recovered by bronchoalveolar lavage from 13 patients with amiodarone pneumonitis. Alveolar macrophages from all patients contained two types of abnormal inclusions: small clear vacuoles and large phagolysosomes containing phospholipid in lamellar structures, abnormalities previously attributed to direct cytotoxicity from amiodarone. However, these changes were always associated with abnormalities in the numbers and types of immune and inflammatory cells present in the lower respiratory tract, which closely resemble those seen in hypersensitivity pneumonitis associated with inhaled antigens. Following discontinuation of amiodarone and institution of corticosteroid therapy, clinical improvement correlated with a return toward normal in the pattern of inflammatory cells present in the lung, although alveolar macrophages continued to display evidence of drug-induced cytotoxicity. These findings support the possibility that a cell-mediated immune response usually plays a role in the pathogenesis of amiodarone pneumonitis, although direct cytotoxicity may predispose these patients to the development of this abnormal immune response.     

Effects of intracoronary beta-radiation therapy after coronary angioplasty: an intravascular ultrasound study

BACKGROUND: Endovascular radiation is emerging as a potential solution for the prevention and treatment of restenosis. Its effects on the morphology of unstented vessels cannot be determined by angiography and therefore require the use of intravascular ultrasound. METHODS AND RESULTS: Through a 5F noncentered catheter for delivery of a 90Sr/Y source train, 12, 14, or 16 Gy at 2 mm was delivered to native coronary arteries after successful balloon angioplasty in 30 patients. Four patients required stent deployment in the first week. Quantitative coronary angiography and IVUS were performed during the initial procedure and at 6-month follow-up. Binary angiographic restenosis was present in 3 of 30 patients, with target lesion and vessel revascularization performed in 3 and 5 patients, respectively. Angiographic late loss was -0.02+/-0.60 mm, with a -0.09+/-0.46 loss index. IVUS demonstrated no significant reduction in lumen area (from 5.69+/-1.72 mm2 after treatment to 6. 04+/-2.63 mm2 at follow-up), with no significant change in external elastic membrane area (13.71+/-4.54 to 14.22+/-4.71 mm2) over the 6-month follow-up. Wall area was 8.01+/-3.85 mm2 after radiation therapy and 8.19+/-3.44 mm2 at follow-up (P=NS). No significant differences were noted between the different dose groups. CONCLUSIONS: beta-Radiation therapy resulted in a low restenosis rate with negligible late loss by angiography. By IVUS, beta-radiation was shown to inhibit neointima formation, with no reduction of total vessel area at 6-month follow-up.     

Detection of cytokeratins in ghost cells of calcifying cystic odontogenic tumor indicates an altered keratinization and hair follicle differentiation for their development

Calcifying cystic odontogenic tumors (CCOTs) are benign cystic lesions of odontogenic origin characterized by an ameloblastoma-like epithelium and the presence of a group of cells named ghost cells. The pattern of cytokeratin (Ck) expression on these lesions remains unclear and needs to be clarified. To this end, the expression of Ck6, Ck13, Ck14, Ck18, and Ck19 in the epithelium lining of 7 cases of CCOTs was evaluated by immunohistochemistry. For this, the epithelium lining was divided into 3 distinct regions: basal layer, suprabasal layer, and the compartment composed of ghost cells. In this study, 6 cases (85.7%) were classified as type 1 and 1 (14.3%) as type 4. All cases were negative for Ck13 and Ck18, despite the epithelial layer, as well as in the ghost cells. Ck6 was only positive in the ghost cells. Positivity for Ck14 and Ck19 was found in the basal and suprabasal layers, including the ghost cells. The results showing positivity for Ck14 and Ck19 in all of the analyzed cases reinforce CCOT as being of odontogenic origin, and the restricted expression of Ck6 in the ghost cells may be indicative that these cells suffer an altered differentiation into hair follicles in CCOTs.     

Transplantation of allogeneic peripheral blood stem cells mobilized by recombinant human granulocyte colony-stimulating factor [see comments]

Peripheral blood stem cells (PBSCs) are widely used in autologous transplantation because of ease of collection and rapid hematopoietic reconstitution. However, PBSCs have rarely been used for allogeneic transplantation because of concerns about donor toxicities from cytokine administration and the theoretical increased risk of graft- versus-host-disease (GVHD) from the large number of T cells infused. Eight patients with advanced malignancies received allogeneic PBSC transplants from genotypically HLA-identical sibling donors. All donors received 5 days of recombinant human granulocyte colony-stimulating factor (rhG-CSF; 16 micrograms/kg/day) subcutaneously and were leukapheresed for 2 days. After treatment of the patient with total body irradiation and cyclophosphamide (n = 7) or etoposide, thiotepa, and cyclophosphamide (n = 1), PBSCs were infused immediately after collection and without modification. All patients received cyclosporine and either methotrexate (n = 6) or prednisone (n = 2) for GVHD prophylaxis, rhG-CSF was well tolerated with mild bone pain requiring acetaminophen occurring in two donors. All patients engrafted and in seven hematopoietic recovery was rapid, with 500 neutrophils/microL achieved by day 18 and 20,000 platelets/microL by day 12. Complete donor engraftment was documented by Y chromosome analysis in all four sex-mismatched donor-recipient pairs tested and by DNA analysis in two sex-matched pairs. One patient died on day 18 of veno-occlusive disease of the liver with engraftment but before chromosome analysis could be performed (results are pending in 1 patient). A second patient died of fungal infection 78 days after transplant. Grade 2 acute GVHD occurred in two patients and grade 3 GVHD occurred in one patient. One patient is 301 days from transplant in remission with chronic GVHD; the remaining five patients are alive and disease free 67 to 112 days after transplantation. Preliminary results indicate that allogeneic PBSCs mobilized by rhG-CSF can provide rapid hematologic recovery without an appreciably greater incidence of acute GVHD than would be expected with marrow. Further follow-up is required to determine the incidence of chronic GVHD and any potential beneficial effects on relapse after transplant.     

Allogeneic peripheral blood stem cell transplantation in patients with advanced hematologic malignancies: a retrospective comparison with marrow transplantation

Allogeneic peripheral blood stem cell (PBSC) transplants from HLA- identical siblings were performed in 37 patients with advanced hematologic malignancies. Outcomes were compared to a historical group of 37 similar patients with advanced hematologic malignancies receiving bone marrow (BM) transplants from HLA-identical donors. The PBSC group and historical BM group were well matched for diagnosis, disease stage, age, and graft-versus-host disease (GVHD) prophylaxis. Patients received PBSC transplants between 1993 to 1995 while BM patients were treated between 1989 to 1994. Engraftment, measured by the time to reach a peripheral neutrophil count > 500/L and platelet count > 20,000/microL without transfusions, occurred on days 14 and 11 in the patients transplanted with PBSC compared to days 16 and 15 in the patients receiving BM (P = .00063, .00014). The PBSC group required a median of 8 U of red blood cells and 24 U of platelets compared to 17 U of red blood cells and 118 U of platelets for BM transplant recipients (P = .0005, .0001). The estimated risks of developing grades 2 to 4 acute GVHD were 37% for the PBSC group and 56% for the BM group (P = .18), while the estimated risks of grades 3 to 4 acute GVHD were 14% for the PBSC group and 33% for the BM group, P = .05). Chronic GVHD occurred in 7 of 18 evaluable patients receiving PBSC and 6 of 23 evaluable patients receiving BM, P = .5. The estimated risks of transplant-related mortality at 200 days were 27% versus 45% (P = .33) relapse were 70% versus 53% (P = .27) and of overall survival were 50% and 41% (P = .39) for patients transplanted with PBSC or BM, respectively. This retrospective comparison suggests that compared to marrow transplantation from HLA-identical donors, allogeneic PBSC transplantation from HLA-identical donors is associated with faster engraftment, fewer transfusions, and no greater incidence of acute or chronic GVHD.     

Transforming growth factor-beta 1 cooperates with anti-immunoglobulin for the induction of apoptosis in group I (biopsy-like) Burkitt lymphoma cell lines

Group I Burkitt lymphoma (BL) cell lines, which retain the original biopsy phenotype, have been shown to enter apoptosis in response to a number of external stimuli including serum deprivation, thermal shock, addition of calcium ionophore, and ligation of surface immunoglobulin (Ig) by antibody. Transforming growth factor-beta 1 (TGF beta 1) is known to cause growth arrest in BL lines. Here we show that while it is by itself capable of promoting some degree of apoptosis in group IBL cells, TGF beta 1 cooperates with anti-immunoglobulin to this end. Trimeric soluble recombinant human CD40 ligand (sCD40L) was able to inhibit apoptosis induced by the combination of agonists to some degree, but such rescue proved to be short-lived. Both TGF beta 1 and anti-Ig individually caused BL cells to undergo growth arrest at the G1 phase of cell cycle before their entry into apoptosis: the consequence of sCD40L addition was to maintain the cells in cycle for longer. No induction of the apoptosis-protecting gene, bcl-2, occurred in the presence of sCD40L. These findings are discussed, particularly highlighting the relationship existing between survival and the cell cycle. The strong cooperative effects observed between anti-Ig and TGF beta 1 in promoting apoptosis and the inability of CD40 to signal for long-term rescue raise the potential for a novel therapeutic attack on B-cell lymphoma.     

ATP diphosphohydrolase in human platelets from patients with coronary arteries heart disease

ATP diphosphohydrolase is an enzyme described in platelets and may be related to the control of ADP-dependent platelet aggregation. Platelet aggregation in atherosclerotic coronary arteries, and the release of platelet-derived factors, play an important role in coronary artery disease syndromes. In this study, we determined the activity of ATP diphosphohydrolase in platelets from patients with chronic and acute coronary artery disease syndromes and healthy persons. The following groups were studied: healthy persons (group I), patients with chronic heart disease (group II) and acute heart disease (group III). Results did not demonstrate differences between the groups studied. The control group demonstrated a lower range of enzyme activity. The patients from groups II and III had ingested drugs with actions upon the cardiovascular system and the effect, in vitro, of these drugs upon the ATP diphosphohydrolase activity in human platelets was also investigated. The in vitro experiments demonstrated that 2.0 mM acetylsalicylic acid inhibited ATP hydrolysis by human platelets by approximately 55%. Significant correlation was observed between ADP hydrolysis and glucose blood levels in the control group and between ATP hydrolysis and triglycerides in the group II. These results contribute to our understanding of a possible relationship between ATP diphosphohydrolase and thrombogenesis.