Ocular gunpowder injury.
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Explosive Agents↗
Biomedical subjects
K Amin
Publications and source records attributed to K Amin.
Characterization of ANIT-induced toxicity using precision-cut rat and dog liver slices cultured in a dynamic organ roller system.
This article describes the toxicity of alpha-naphthylisothiocyanate (ANIT), a compound known to induce dose-dependent hepatobiliary toxicity in vivo, using the slice model. Liver slices (200 microm thick) from male Sprague-Dawley rats and male beagle dogs were cultured for 7 days while exposed to a range of ANIT concentrations (1- 100 microM for rat and 4-320 microM for dog). Tissues (and medium for dog) were evaluated using a panel of clinically relevant biomarkers for liver and histological endpoints to assess viability and proliferation. ANIT increased slice levels of enzyme biomarkers corresponding to biliary markers. At high concentrations (80-100 microM for rat, 320 microM for dog) a diminution of tissue enzyme levels was observed, corresponding to severe hepatobiliary injury. By days 5 and 7, biochemical markers in the medium of dog slices indicated an elevation of hepatocellular and biliary markers. Histologically for both species, minimal hepatocellular injury was noted, but proliferation of biliary epithelial cells (BEC) was observed using 5-bromo-2-deoxyuridine (BrdU) immunostaining. In rat slices, ANIT increased the expression of inducible nitrous oxide synthase (iNOS) within 12 hrs of exposure. In summary, additional experimentation using slice culture may further demonstrate its value in screening compounds that cause hepatobiliary toxicity.
1-Naphthylisothiocyanate↗
In vitro detection of differential and cell-specific hepatobiliary toxicity induced by geldanamycin and 17-allylaminogeldanamycin in rats.
The differential toxicity of two anticancer agents is described using the in vitro rat liver slice culture model. Liver slices from F-344 rats were cultured for 5 days in Waymouth's-based medium with exposure to a range of geldanamycin (GEL) or 17-allylaminogeldanamycin (17-AAG) concentrations. GEL induced concentration-dependent reduction of alkaline phosphatase and of gamma-glutamyl transferase levels, which are indicators of biliary epithelial cell(s) (BEC) viability, and exhibited hepatocellular toxicity at higher concentrations. Histologically, BEC cell injury was evident at the lowest GEL concentration (0.1 microM) and progressed to overt bile duct necrosis at 5 microM, a level at which hepatocellular damage was also more prominent. Slices exposed to the same concentrations were more sensitive to toxic effects of GEL than of 17-AAG. 17-AAG at the lowest concentration had more slice biomarker retention than GEL, and histological analysis revealed minimal toxic effect on BEC. With increasing concentration, BEC were progressively lost, and BEC proliferation was completely inhibited at 5 microM 17-AAG. Hepatocellular injury was evident only at high dose exposures. This is believed to be the first use of an in vitro liver tissue model to accurately predict the differential and concentration-dependent toxicities of these compounds.
Alanine Transaminase↗
Eosinophil granulocytes are activated during the remission phase of ulcerative colitis.
AIM: The aim of this study was to establish a method of investigating intestinal eosinophil and neutrophil granulocytes by flow cytometry, and to compare the distribution and activity of these cells in different stages of ulcerative colitis (UC). METHODS: Biopsy samples were taken from six locations of the entire colon and from the terminal ileum in 10 patients with active total UC, 10 patients with inactive total UC, eight patients with active distal UC, and 11 control subjects. Cell suspensions from biopsies and from peripheral blood were incubated with fluorophore conjugated monoclonal antibodies. The use of scatter plot-gating and specific antibodies was established in a flow cytometry assay. RESULTS: Eosinophils were more numerous and more active in patients with active UC than in controls. Interestingly, during inactive UC, the number of activated eosinophils was even larger. Eosinophil activity was high in the rectum of patients with distal colitis but was also slightly elevated in the proximal colon. Neutrophils were increased in number and activity during active but not inactive UC. In patients with distal colitis, activated neutrophils were only found in the sigmoid colon and rectum. CONCLUSION: With this method, we confirm that neutrophils participate in the inflammatory process during active UC, and that they express a resting phenotype during remission. The finding of activated eosinophils in inflamed intestine strengthens the view of these cells as proinflammatory and tissue damaging. Nevertheless, our new finding of high eosinophil activation during inactive UC suggests that eosinophils play a role in repair of injured epithelium.
Adult↗
Bronchial mucosal mast cells in asymptomatic smokers relation to structure, lung function and emphysema.
The pathologic mechanisms of chronic obstructive pulmonary disease (COPD) most certainly involves neutrophil granulocytes, cytotoxic T-cells, macophages and mast cells. The aim of this study was to investigate the relation between the number of mast cells in different compartments in bronchial biopsies of central proximal airways to structural changes, lung function tests and emphysema detected by high resolution computed tomography (HRCT). Twenty nine asymptomatic smoking and 16 never-smoking men from a population study were recruited. Central bronchial biopsies were stained to identify mast cells by immunohistochemistry. The number of mast cells in the epithelium, lamina propria and smooth muscle as well as epithelial integrity and thickness of the tenascin and laminin layer were determined. Smokers had increased numbers of mast cells in all compartments (P<0.001). Structural changes were correlated to mast cell numbers with the closest associations to mast cell numbers in the smooth muscle [epithelial integrity (R(S)=-0.48, P=0.008), laminin layer (R(S)=0.63, P=0.0002), tenascin layer (R(S)=0.40, P=0.03)]. Similar correlations between mast cells and lung function tests were seen [functional residual capacity (FRC) (R(S)=0.60, P=0.0006), total lung capacity (TLC) (R(S)=0.44, P=0.02) and residual volume (RV) (R(S)=0.41, P=0.03)]. No correlations could be detected between mast cells and FEV1 or to emphysema. Smoking is associated with an increase of mast cells in all compartments of the bronchial mucosa, including smooth muscle, and this is related to altered airway structure and function.
Aged↗
The extracellular deposition of mast cell products is increased in hypertrophic airways smooth muscles in allergic asthma but not in nonallergic asthma.
BACKGROUND: Bronchial asthma is characterized by airways smooth muscle hypertrophy and infiltration of mast cells in the bronchial mucosa. The aim of this investigation was to study the distribution of mast cells in different compartments in the bronchial mucosa of allergic and nonallergic asthma in relation to airways remodeling. METHODS: Bronchial biopsies were obtained from 29 subjects with allergic and nonallergic asthma and healthy controls. The biopsies were stained for mast cells by means of the tryptase specific antibody AA1. Extracellular deposition of mast cell products were judged on a semi-quantitative scale. Mast cells per mm(2) were counted in epithelium, lamina propria and the smooth muscle compartment. Smooth muscle was visualized by actin antibodies and the proportion of staining of the biopsy estimated. Laminin and tenascin layers were visualized by their respective antibodies. RESULTS: Airways smooth muscle thickness was greater in allergic vs nonallergic asthma (P < 0.001). Mast cells were increased in all three compartments in both allergic and nonallergic asthma, with significantly higher numbers in smooth muscles in allergic asthma (P < 0.03). The extracellular deposition of mast cell products was more common in allergic than nonallergic asthma in lamina propria and smooth muscles (P = 0.025; P = 0.002, respectively). In patients with allergic asthma the numbers of mast cells with extracellular deposition of mast cell products were significantly correlated to the thickness of the laminin and tenascin layers. CONCLUSION: Our results suggest that there are large differences between allergic and nonallergic asthmatics as to mast cell activation and airways smooth muscle thickness. Our data implies that mast cells are causally involved in structural alterations in allergic asthma.
Adult↗
Safety and outcome after fludarabine-thiotepa-TBI conditioning for allogeneic transplantation: a prospective study of 30 patients with hematologic malignancies.
Fludarabine, thiotepa and total body irradiation (TBI) has been used as conditioning in haplo-identical transplantation. We studied this conditioning regimen in adults undergoing matched sibling transplantation and alternative donor transplantation. A total of 30 consecutive patients underwent matched related, haplo-identical related or matched unrelated donor transplantation with fludarabine, thiotepa and TBI conditioning. All but four had advanced hematologic malignancies. For haplo-identical transplant, ATG was added to the regimen. All patients received peripheral blood stem cells; these were T-cell depleted for 2-antigen or 3-antigen mismatched related transplantation. Additional graft-versus-host disease prophylaxis consisted of tacrolimus and mini-methotrexate. One recipient of haplo-identical transplant failed to engraft; all other evaluable patients had prompt engraftment. Four patients died of regimen-related toxicity. In all, 14 additional patients died of regimen-related causes including four from failure to thrive with persistent thrombocytopenia and four from delayed pulmonary toxicity. Six patients relapsed. Progression-free survival at 12 months was 47% (90% CI: 25-69%) for recipients of HLA-identical sibling transplants and 30% (90% CI: 14-46%) for all patients. Five of six long-term survivors have extensive chronic GVHD. As a result of the delayed complications and a relatively high recurrence rate, we abandoned this regimen.
Adolescent↗
Regimen-related toxicity after fludarabine-melphalan conditioning: a prospective study of 31 patients with hematologic malignancies.
A total of 31 consecutive patients with hematologic malignancies who were considered poor candidates for TBI underwent allogeneic stem cell transplantation after conditioning with fludarabine and melphalan. A total of 25 matched sibling recipients received fludarabine 25 mg/m(2) x 5 days and melphalan 70 mg/m(2) x 2 days. For unrelated and haploidentical donor recipients, fludarabine was increased to 30 mg/m(2) and ATG 30 mg/kg x 4 days was added. Graft-versus-host disease prophylaxis consisted of tacrolimus and mini methotrexate. All patients engrafted. Regimen-related toxicity was considerable and included mainly renal, hepatic and mucosal toxicity. There were seven regimen-related-deaths including two VOD, two pulmonary, one renal, one cardiac and one mucosal toxicity. One case of fatal pulmonary toxicity death could be attributed to pre-existing pulmonary damage. Progression-free survival at 12 months was 44% (90% CI: 30-58%) for recipients of HLA-identical sibling transplants and 33% (90% CI: 21-45%) for all patients. In conclusion, the fludarabine-melphalan regimen leads to consistent engraftment. The regimen-related toxicity is considerable and cannot be explained solely by patient selection. Cardiac toxicity is emerging as a unique toxicity of this regimen. Despite toxicity, fludarabine-melphalan has considerable activity and leads to durable remission in a proportion of patients.
Antineoplastic Combined Chemotherapy Protocols↗
Relationship between inflammatory cells and structural changes in the lungs of asymptomatic and never smokers: a biopsy study.
BACKGROUND: A study was undertaken to investigate the relationship between inflammatory cells and structural changes in the mucosa of the airways in an epidemiological sample of a group of asymptomatic smokers (smokers who had never sought medical attention for respiratory problems) and in non-smoking subjects. METHODS: Bronchial biopsy specimens were taken from 29 smokers and 16 never smokers and stained with monoclonal antibodies HNL, EPO, AA1, CD68 in order to identify neutrophils, eosinophils, mast cells, and macrophages, respectively. The biopsy specimens were also stained with monoclonal antibodies to the cytokines interleukin (IL)-1beta and IL-8. Structural changes were identified by staining the biopsy specimens with antibodies to tenascin and laminin and by evaluating the condition of the epithelial layer. RESULTS: The numbers of all inflammatory cells and of cytokine staining cells were significantly increased in smokers. The thickness of the tenascin and laminin layers was increased in the smoking group and the integrity of the epithelial layer was significantly reduced. In smokers the epithelial integrity was negatively correlated with the number of eosinophils and macrophages. The thickness of the tenascin and laminin layers was positively correlated with AA1 and EPO positive cells only. CONCLUSION: High numbers of inflammatory cells are present in the bronchial mucosa of asymptomatic smokers which have a clear relationship with the impaired epithelial integrity. The increased thickness of the laminin and tenascin layers in these subjects was strongly related to the presence of eosinophils and mast cells, suggesting a role for these cells in tissue remodelling of the airways of smokers.
Adult↗
Tissue gradients of energy metabolites mirror oxygen tension gradients in a rat mammary carcinoma model.
PURPOSE: It has been shown that oxygen gradients exist in R3230AC tumors grown in window chambers. The fascial surface is better oxygenated than the tumor surface. The purpose of the present study was to determine whether gradients exist for energy metabolites and other end points related to oxygen transport. METHODS AND MATERIALS: Imaging bioluminescence was used to measure ATP, glucose, and lactate in cryosections of R3230AC tumors. Mean vessel density and hypoxic tissue fraction were assessed using immunohistochemistry. Tumor redox ratio was assessed by redox ratio scanning. RESULTS: Lactate content and hypoxic fraction increased, whereas ATP, glucose, redox ratio, and vessel density decreased from the fascial to the tumor surface. CONCLUSIONS: The data support a switch from aerobic to anaerobic metabolism concomitant with the PO2 gradient. The vascular hypoxia that exists in perfused vessels at the tumor surface leads to macroscopic tissue regions with restricted oxygen availability and altered metabolic status. Methods to reduce tumor hypoxia may have to take this into account if such gradients exist in human tumors. The results also have implications for hypoxia imaging, because macroscopic changes in PO2 (or related parameters) will be easier to see than PO2 gradients limited to the diffusion distance of oxygen.
Adenosine Triphosphate↗
Radiation-induced hypoxia may perpetuate late normal tissue injury.
PURPOSE: The purpose of this study was to determine whether or not hypoxia develops in rat lung tissue after radiation. METHODS AND MATERIALS: Fisher-344 rats were irradiated to the right hemithorax using a single dose of 28 Gy. Pulmonary function was assessed by measuring the changes in respiratory rate every 2 weeks, for 6 months after irradiation. The hypoxia marker was administered 3 h before euthanasia. The tissues were harvested at 6 weeks and 6 months after irradiation and processed for immunohistochemistry. RESULTS: A moderate hypoxia was detected in the rat lungs at 6 weeks after irradiation, before the onset of functional or histopathologic changes. The more severe hypoxia, that developed at the later time points (6 months) after irradiation, was associated with a significant increase in macrophage activity, collagen deposition, lung fibrosis, and elevation in the respiratory rate. Immunohistochemistry studies revealed an increase in TGF-beta, VEGF, and CD-31 endothelial cell marker, suggesting a hypoxia-mediated activation of the profibrinogenic and proangiogenic pathways. CONCLUSION: A new paradigm of radiation-induced lung injury should consider postradiation hypoxia to be an important contributing factor mediating a continuous production of a number of inflammatory and fibrogenic cytokines.
Animals↗
LDL-induced association of anionic liposomes with cells and delivery of contents. II. Interaction of liposomes with cells in serum-containing medium.
In the present study we have investigated cell binding and drug delivery potency of various anionic liposomal formulations in a serum-supplemented growth medium, in order to understand the role of the LDL receptor in targeted drug delivery mediated by anionic liposomes. The cell lines used were CV1-P and CHO wild type, which both express the LDL receptor, and CHOldlA7, which lacks the LDL receptor. Cellular association of encapsulated methotrexate and fluorescein labeled phosphatidylethanolamine in the lipid bilayer was measured. Potency of two liposome-dependent drugs (N-phosphonacetyl-L-aspartic acid and fluoroorotic acid) was also measured by growth inhibition. Association of ePG liposomal aqueous contents with cells grown in serum-supplemented growth medium was up to 30-fold higher with CV1-P or CHO wild type cells than with CHOldlA7. Increased association was not paralleled by a corresponding increase in potency of liposome-dependent drugs. The serum-dependent association of fluid, anionic (ePG) liposomes with cells expressing the LDL receptor is caused by an interaction of ePG liposomes with LDL. The failure of this association to increase drug delivery seems to be caused by the downregulation of LDL receptor expression when cells are continuously exposed to LDL.
Animals↗
LDL induced association of anionic liposomes with cells and delivery of contents as shown by the increase in potency of liposome dependent drugs.
PURPOSE: To establish whether anionic liposomes interact with the low-density lipoprotein (LDL) receptor, to determine the role of lipoproteins in this interaction, and whether the association causes functional delivery of encapsulated drugs. METHODS: The cell lines used were CV1-P and CHO wild type, both of which express the LDL receptor, and CHOldlA7, which lacks the LDL receptor. Cellular association of encapsulated methotrexate and fluorescein, labeled phosphatidylethanolamine in the lipid bilayer, was measured. Potency of three liposome dependent drugs (N-phosphonacetyl-L-aspartic acid, fluoroorotic acid, and methotrexate-gamma-aspartate) was also measured by growth inhibition. RESULTS: Association of liposomes containing at least 75 mol egg phosphatidylglycerol (ePG)/100 mol phospholipid with cells grown in defined medium supplemented with 1.0 mg/ml LDL was up to 30-fold higher with CV1-P or CHO wild type cells than with CHOldlA7, and 5-fold higher than association in defined medium lacking LDL. The addition of LDL did not yield any elevation of cellular association of distearoylphosphatidylglycerol liposomes. Increased association was paralleled by a corresponding increase in potency of all three liposome dependent drugs tested. CONCLUSIONS: ePG liposomes interact with the LDL receptor in an LDL-dependent fashion, and the interaction results in the delivery of contents to cells.
Animals↗
Fludarabine and melphalan-based conditioning for patients with advanced hematological malignancies relapsing after a previous hematopoietic stem cell transplant.
Severe regimen-related toxicity often complicates second transplant procedures performed in patients with hematological malignancies that have relapsed after an initial hematopoietic stem cell (HSC) transplant. Therefore, we studied the safety and efficacy of a reduced-intensity fludarabine and melphalan based conditioning regimen in 11 patients who had relapsed following an autologous (n = 7) or allogeneic (n = 4) HSC transplant. All patients received allogeneic peripheral blood HSC from either an HLA-identical (n = 7) or an HLA-mismatched (n = 4) relative. Diagnoses included AML (n = 9), ALL (n = 1), or Hodgkin's disease (n = 1). Only one patient was in complete remission at the time of second transplant. The median interval between first transplant and relapse was 163 days (range 58-1885). Recipients of HLA-mismatched transplants received antithymocyte globulin in addition to fludarabine and melphalan as part of the conditioning regimen. All 11 patients received acute GVHD prophylaxis consisting of tacrolimus and methotrexate. Ten of 11 patients achieved hematopoietic engraftment with a median time to absolute neutrophil count >0.5 x 10(9)/l and to platelet count of >20 x 10(9)/l of 14 and 19 days, respectively. All engrafting patients achieved 100% donor chimerism on initial analysis, except for one with persistent leukemia at day +19. Two patients experienced grade 3 regimen-related toxicity, manifesting as acute renal failure. Acute GVHD grades 2-4 occurred in two recipients and chronic GVHD in four. The 100-day mortality from all causes was 36%. Ten of 11 patients (91%) died a median of 140 days (range 9-996) after the second transplant. The causes of death included relapse (n = 5), sepsis (n = 4), and idiopathic pneumonia syndrome (n = 1). One patient with AML survives in remission at 880 days post-transplant. We conclude that fludarabine- and melphalan-based conditioning promotes full donor chimerism, even following HLA-mismatched transplants. However, the regimen may be more beneficial when applied to patients undergoing allogeneic HSC transplantation earlier in their disease course.
Adult↗
Inclusion of the herpes simplex thymidine kinase gene in a replicating adenovirus does not augment antitumor efficacy.
Replication-incompetent adenoviruses (Ad) carrying the herpes simplex thymidine kinase (HSVtk) gene have been used in a number of human cancer gene therapy trials, however transduction has generally been limited to a small minority of tumor cells. To solve this problem, replication-competent adenoviral vectors carrying transgenes such as HSVtk have been developed. However, contradictory evidence exists regarding the efficacy of these new vectors. Accordingly, we constructed and tested a replication-competent E3-deleted adenoviral vector containing the HSVtk suicide gene driven by the endogenous E3 promoter (Ad.wt.tk). This virus showed high level production of the HSVtk transgene and was more efficacious than a non-replicating virus in vitro, after injection into flank tumors, and against established intraperitoneal tumors. However, addition of ganciclovir (GCV) therapy to cells or tumor-bearing animals treated with the replicating vector containing the HSVtk suicide gene did not result in increased cell killing. Our results indicate that addition of HSVtk to a replicating Ad virus will not likely be useful in augmenting antitumor effects.
Adenoviridae↗
Inflammation and structural changes in the airways of patients with primary Sjögren's syndrome.
The present study aimed to compare the cellular pattern and structural changes in the airways of patients with primary Sjögren's syndrome (pSS) with healthy controls. Bronchial biopsy specimens were obtained from seven subjects with pSS and seven healthy controls. All the patients with pSS had increased bronchial responsiveness to methacholine. In the biopsies inflammatory cells, cytokine-producing cells, tenascin and laminin were visual zed by immunostaining. Patients with pSS had a higher number of neutrophils and mast cells than healthy controls, while the number of eosinophils was similar in the two groups. The number of IL-8-positive cells was higher in pSS butthe numbers of IL-4-and IL-5-positive cells were not significantly different between pSS and healthy controls. The numbers of T cells in patients with pSS were higher than in healthy controls, while the numbers of CD25-positive cells were similar to the healthy controls. The degree of epithelial integrity in patients with pSS was significantly lower than in the control group and the tenascin and laminin layers were significantly thicker in the pSS group. There was a correlation between the number of mast cells and the thickness of the tenascin and laminin layers in pSS. In conclusion, we found that the cellular pattern in the bronchial mucosa of patients with pSS displayed large numbers of neutrophils, mast cells and T-lymphocytes. These changes in inflammatory cell numbers seemed to relate to the observed increased epithelial damage and structural changes of the subepithelium. The structural findings, but not the pattern of inflammatory cells, are shared with atopic asthma and may relate to the increased bronchial hyper-responsiveness seen in both diseases.
Adult↗
Inflammatory cell and epithelial characteristics of perennial allergic and nonallergic rhinitis with a symptom history of 1 to 3 years' duration.
BACKGROUND: Perennial rhinitis is an inflammatory condition of the mucosal lining of the nose that may be caused by allergic and nonallergic mechanisms. OBJECTIVE: We sought to characterize the cellular pattern and structural changes in the nasal mucous membrane of patients with perennial rhinitis and compare them with those of control subjects. METHODS: Biopsy specimens were obtained from 27 patients with perennial allergic rhinitis (PAR), from 12 patients with perennial nonallergic rhinitis (PNAR) with eosinophils present in the nasal smear, and from 6 control subjects without rhinitis. In 10 of 27 patients with PAR who were also allergic to pollen, biopsy specimens were taken within the respective season (PARseason). In the other 17 patients, the biopsy was taken outside the pollen season (PARoutside season). Inflammatory cells were identified by using mAbs to their unique granular proteins. RESULTS: The characteristic feature of perennial rhinitis was the accumulation of activated (degranulated) mast cells and eosinophils in the nasal mucosa. The tissue eosinophil/neutrophil ratio was higher, and the loss of epithelial integrity was greater in all patient groups compared with the control subjects. The extent of epithelial damage was significantly larger in patients in the PARseason group compared with that in the PARoutside season and PNAR groups, which did not significantly differ from each other in this respect. The number of eosinophils and mast cells was higher in the PNAR group compared with the PAR groups. In all patient groups, the number of eosinophils correlated with the loss of epithelial integrity. The number of mast cells did not correlate with the extent of epithelial damage nor did the number of neutrophils, except in patients in the PARseason group. CONCLUSION: The accumulation of eosinophils and mast cells, as well as loss of epithelial integrity, was characteristic for perennial rhinitis. Loss of epithelial integrity in the nasal mucosa may be a consequence of the activity of accumulated eosinophils.
Adult↗
Lymphoscintigraphy using (99m)Tc filtered sulfur colloid in chylothorax: a case report.
OBJECTIVE: A 66-y-old man was diagnosed with esophageal carcinoma and underwent a right thoracotomy and esophagectomy. Postoperatively, a recurring right pleural effusion developed. Because an attempt at lymphangiography failed, lymphoscintigraphy was suggested. Because of the inability to obtain radiolabeled albumin, dextran, or nanocolloid, we used filtered sulfur colloid. (0.1 um). The study confirmed the diagnosis of chylothorax.
Aged↗