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PubMed1990

Transplantation studies in mice with congenital hemolytic anemia.

Sphha/sphha anemic mice have an abnormality in the erythroid membrane protein, alpha spectrin, and exhibit multiple related clinical abnormalities, including spherocytosis, shortened red cell survival, chronic hemolysis, hemosiderosis, and extramedullary hematopoiesis. In addition, these mutant mice exhibit a granulocytosis and lymphocytosis, lymph node hyperplasia, elevated serum immunoglobulins, membranoproliferative glomerulonephritis, and decreased lifespan--abnormalities that are less clearly attributable to a spectrin defect. In order to further elucidate the mechanisms of disease in these animals, we undertook a series of bone marrow transplantation experiments. Transplantation of anemic marrow into lethally irradiated congenic +/+ mice resulted in chronic spherocytosis, hemolytic anemia, peripheral leukocytosis, and extramedullary hematopoiesis. Additionally, transplant recipients of anemic marrow which had received a higher radiation dose (12 Gy) had increased numbers of peripheral blood CD4+ and CD8+ lymphocytes, a hypocellcular thymus, and a severe pneumonitis characterized by nodular areas of consolidation and edema. Mice receiving congenic +/+ marrow and irradiated with the same radiation dose exhibited minimal pulmonary abnormalities. Anemic mice transplanted with congenic +/+ marrow usually died, but the survivors exhibited reversal of some clinicopathological changes. These results would suggest that the clinical abnormalities of sphha/sphha mice are in part attributable to abnormalities of hematopoietic stem cells but may also involve defects in other cell types. The pathogenesis of the accompanying lymphoid abnormalities observed in this mutant anemic mouse and any correlation with the erythroid spectrin defect are presently unknown. The pulmonary disease that develops in the transplant recipients of anemic marrow needs to be characterized further but may represent a unique model of lung injury.

Anemia, Hemolytic, Congenital↗
PubMed1986

Assessment of toxicity of o-nitrochlorobenzene in rats following a 4-week inhalation exposure.

o-Nitrochlorobenzene (ONCB) is a chemical intermediate used for the synthesis of various industrial chemicals. To evaluate the subchronic toxicity of this compound, three groups of 15 male and 15 female Sprague-Dawley rats were exposed to ONCB vapor 6 hr/day, 5 days/week for 4 weeks at target concentrations of 10, 30, or 60 mg/m3. A control group of 15 animals/sex was exposed to room air in a separate inhalation chamber. Concentrations of ONCB in the chambers were determined at least three times a day using a uv spectrophotometer. Parameters monitored in this study included observation for signs of toxicity, body weights, ophthalmoscopic exam, hematology, and clinical chemistry. At necropsy, selected organ weights were recorded and over 35 tissues/animal were examined microscopically for all control and high-exposure level animals. No mortality was observed in this study. Mean body weights of all groups were comparable to controls. Animals exposed to the mid and high concentrations of ONCB showed a significant increase in blood methemoglobin and a significant decrease in hemoglobin, hematocrit, and red blood cell counts. Spleen and liver weights (absolute and relative to body weight) were significantly increased for these two groups. Microscopic changes, observed only in the spleen, included increased degree of extramedullary hematopoiesis and hemosiderosis. These data suggest that the toxicity of ONCB is comparable to that of its structural analog, p-nitrochlorobenzene. Thus these two compounds should have similar work-place exposure limits.

Administration, Inhalation↗
PubMed1990

Comparative toxicity of arsine gas in B6C3F1 mice, Fischer 344 rats, and Syrian golden hamsters: system organ studies and comparison of clinical indices of exposure.

In order to examine possible species differences in response to arsine exposure, multiple inhalation studies consisting of acute (1-day), subacute (14- and 28-day), and subchronic (90-day) exposures to this agent were conducted using three different species of rodents. Evaluations of hematopoietic organs and alterations in the heme biosynthetic pathway were the focus of these studies. Species used were B6C3F1 mice (exposed 1, 14, or 90 days), Fischer 344 rats (exposed 14, 28, or 90 days), and Syrian Golden hamsters (exposed 28 days). All arsine exposures were at concentrations of 0.5, 2.5, or 5.0 ppm except for 90-day studies, in which concentrations were lowered to 0.025, 0.5, or 2.5 ppm. No changes in body weight gain were observed in either sex of mice or hamsters. The only decrease in body weight gain occurred in male rats exposed to 5.0 ppm arsine for 28 days. Significant exposure-related increases in relative spleen weights occurred in both sexes of mice and rats in the 0.5 (except 14-day female rats), 2.5, and 5.0 ppm exposure groups from all studies and in hamsters in the 2.5 and 5.0 ppm exposure groups. Generally, increases in relative liver weight occurred in fewer exposure groups and were of a lesser magnitude than increases in spleen weight. Other parameters affected included decreased packed cell volumes (mice, rats, and hamsters), hematology profiles (rats), and an increase in delta-aminolevulinic acid dehydratase activity in all species. Arsenic content was measured in livers of rats after 90 days of exposure. Concentrations increased in relation to atmospheric concentrations of arsine. Histopathologic changes included increased hemosiderosis and extramedullary hematopoiesis in spleen and intracanalicular bile stasis (mice only) in liver. Additionally, bone marrow hyperplasia was observed in rats. Effects on other organs were not observed, suggesting that the hematopoietic system is the primary target for arsine. In conclusion, we have determined that the effects of arsine exposure upon mice, rats, and hamsters are similar. Most importantly, even though no effects on the hematopoietic system were observed following a single exposure to 0.5 ppm arsine which is 10 times the Threshold Limit Value (TLV) set by the American Conference of Governmental Industrial Hygienists, repeated exposure to 0.025 ppm (one-half the TLV) caused a significant anemia in rats.

Administration, Inhalation↗
PubMed1992

Three-month effects of MDL 19,660 on the canine platelet and erythrocyte.

Nine male and nine female Beagle dogs were divided into three groups and administered orally 0, 15, or 30 mg/kg/day of the antidepressant compound MDL 19,660(5-(4-chlorophenyl)-2,4-dihydro-2,4-dimethyl-3H-1,2,4-triazole-3-t hione) for 3 months to determine the long-term effects on hemopoietic cells. Compared to a control platelet range of 353,000-452,000/microliters, a thrombocytopenia reached lowest mean levels of 135,000/microliters in the 15 mg/kg/day dogs after 2 weeks and 81,000/microliters in the 30 mg/kg/day dogs after 1 week. Subsequently, platelet numbers progressively increased and by the end of the study averaged 222,000/microliters and 203,000/microliters in dogs administered 15 and 30 mg/kg/day. Ultrastructural study of the platelet increase in the 30 mg/kg/day dogs revealed more smaller discoid platelets but no change in percentage platelets with vacuolar degeneration. Histologically, megakaryocyte hyperplasia was present in the sternal marrows and spleens of treated dogs. These observations suggest that increased thrombopoiesis rather than reduced destruction was involved in this partial recovery of platelet numbers during continuous treatment. Concurrently, cyclic formation of reticulocytes and Heinz bodies occurred in dogs given 30 mg/kg/day of MDL 19,660. These dogs had slightly lower erythrocyte counts, hemoglobin levels, and hematocrits in association with hemosiderosis (spleen, liver), extramedullary hematopoiesis (spleen), and bone marrow hypercellularity. These findings indicate that both destructive and regenerative processes followed MDL 19,660-induced Heinz body formation.

Animals↗
PubMed1985

Carcinogenesis of 4-aminobiphenyl in BALB/cStCrlfC3Hf/Nctr mice.

Male and female (840 each) BALB/cStCrlfC3Hf/Nctr mice were given 0, 7, 14, 28, 55, 110 and 220, and 0, 7, 19, 38, 75, 150 and 300 ppm, respectively, of 4-aminobiphenyl in their drinking water. Necropsies on killed animals were performed at 13, 26, 39, 52 and 96 weeks on dose. Dose-related neoplasms were angiosarcomas, bladder urothelial carcinomas and hepatocellular neoplasms. The non-neoplastic dose-related lesions were left atrial thrombosis, bladder urothelial hyperplasia, splenic hemosiderosis and splenic erythropoiesis. The incidences of bladder carcinoma and atrial thrombosis were higher in the males and the incidences of hepatocellular neoplasms and angiosarcomas were higher in the females.

Aminobiphenyl Compounds↗
PubMedDate not supplied

Emergency radiology of the pediatric chest.

This monograph will present an overview of pediatric emergency room chest radiology. Technique, interpretative approach, normal radiologic appearances, common normal variants, and unique features of the pediatric lung are discussed. The radiologic features of common pediatric chest emergencies (infection, airway foreign body, asthma, hydrocarbon aspiration, near-drowning pneumothorax, trauma, hemosiderosis and upper airway obstruction) are described and illustrated.

Child↗
PubMedDate not supplied

MR findings in hereditary spherocytosis.

The magnetic resonance findings of intrathoracic extramedullary hematopoiesis associated with bone marrow reconversion, and reticuloendothelial hemosiderosis in a 50-years-old are reported. Radiologic finding of extramedullary hematopoiesis was the first step to the diagnosis of previously unknown hereditary spherocytosis.

Bone Marrow↗
PubMed2006

Medroxyprogesterone - valproic acid - aspirin. MVA regime to reduce transfusion associated mortality in late-term hemoglobinopathies. Hypothesis and rationale.

Medroxyprogesterone acetate (MPA) - a safe depot contraceptive - is shown previously to reduce painful crises of sickle cell anemia, which is parallel with the recent findings showing progesterone induction of fetal hemoglobin genes. This would be a way to reduce transfusions for late term thalassemia major and sickle cell-disease cases with no chances left for a stem cell transplantation. In these patients, transfusional hemosiderosis causes irreversible damage to many organs despite the available iron-chelating agents. Pharmacological strategies either target the conformal structure of the defective adult hemoglobin or aim to activate fetal hemoglobin concentrations. The only concern on MPA may be its thromboembolic risks, which may be uncoupled with agents acting both anti-coagulant and inductive on the blood oxygen-carrying affinity. Such agents could be valproic acid and aspirin. Valproic acid is being safely used to treat epilepsy and its histone acetylating function may lead its induction of fetal hemoglobin. Aspirin was shown to increase oxygen affinity of hemoglobin via acetylating lysine residues and its general acetylating activity on proteins such as histones makes it also an interesting candidate to activate fetal hemoglobin. We propose that combining MPA with clinically available doses of valproic acid and aspirin would be beneficial in terms of both reduced coagulation risks and increased oxygen affinity to decrease the transfusions and to improve the prognosis in late-phase hemoglobin disorders.

Aspirin↗
PubMed1978

Radiographic aspects of occult pulmonary haemorrhage.

Patients with leukaemia, on anticoagulant therapy, or with disseminated intravascular coagulation may develop occult pulmonary haemorrhage; it will mimic pulmonary oedema, pulmonary hemosiderosis or opportunistic infections. It can be diagnosed by bronchopulmonary lavage. The radiographic changes are described and the differential diagnosis discussed in a series of 12 such patients.

Adolescent↗
PubMed1997

Histopathologic impact of GB virus C infection on chronic hepatitis C.

BACKGROUND & AIMS: Dual infection by hepatitis GB virus type C (GBV-C) and hepatitis C virus (HCV) is common. To assess the histopathologic impact of GBV-C infection on liver lesions, liver biopsy specimens of 105 patients chronically infected with HCV, 17 of whom (15%) were also infected with GBV-C, were reviewed. METHODS: Semiquantitative histopathologic assessment of liver lesions was performed using the Knodell's score and the METAVIR grading system. RESULTS: Hepatitis activity was mild, moderate, or severe in 3 (18%), 11 (64%), and 3 (18%) patients, respectively, infected with GBV-C and HCV vs. 26 (29%), 56 (64%), and 6 (7%) patients, respectively, infected with HCV alone (no significant difference). Cirrhosis was present in 4 (24%) coinfected patients vs. 19 (22%) HCV-positive patients (no significant difference). No significant difference in fibrosis, presence of portal lymphoid aggregates, steatosis, and hemosiderosis was observed between the two groups. There was no significant difference in the evaluation of each item of the Knodell's score. CONCLUSIONS: This detailed histopathologic evaluation of GBV-C infection in chronic hepatitis C shows that GBV-C infection does not affect histopathologic severity and characteristics of chronic hepatitis C, thus suggesting a minor role of GBV-C infection in liver disease.

Adult↗
PubMed1979

A new syndrome of refractory sideroblastic anemia with vacuolization of marrow precursors and exocrine pancreatic dysfunction.

In the past decade, we have studied four unrelated children with what we believe is a previously unreported disorder affecting the bone marrow and exocrine pancreas. During infancy these patients had the onset of severe, transfusion-dependent, macrocytic anemia plus a variable degree of neutropenia and thrombocytopenia. Their bone marrows had normal cellularity but were characterized by remarkable vacuolization of erythroid and myeloid precursors, hemosiderosis, and ringed sideroblasts. The vacuoles probably represented manifestations of cellular degeneration and death. In two patients, in vitro bone marrow cultures showed abnormal erythroid and myeloid progenitor cell growth and, in one child, abnormal vacuolated erythroid colonies. Family histories were unrevealing, parents were hematologically normal, and both sexes were involved. There was no evidence of specific nutritional deficiencies or exposure to agents associated with marrow vacuolization. A number of therapeutic interventions produced no effect. One child had clinical malabsorption. This child and one other had extensive pancreatic fibrosis at autopsy. The other two patients had findings indicating exocrine pancreatic dysfunction. Two children had splenic atrophy. This new syndrome, with associated bone marrow and exocrine pancreatic dysfunctions, differs in several respects from the syndrome of pancreatic liposis and neutropenia described by Shwachman et all and Bodian et al, and from other conditions with vacuolization of the marrow or sideroblastosis.

Anemia, Sideroblastic↗
PubMed1981

Chelation therapy in beta-thalassemia major. III. The role of splenectomy in achieving iron balance.

Transfusion requirements for 1978 were compiled for 79 patients with thalassemia major (ages 1 to 29 years) who were maintained at hemoglobin concentrations of greater than 10 gm/dl. In 46 patients with intact spleens, the mean transfusion requirement was 258 ml/kg/year, and there was a clear increase with age. The transfusion history prior to 1978 had no influence on the increase of transfusion requirement with age. In contrast, in 33 splenectomized patients, the mean transfusion requirement was 203 ml/kg/year and it did not increase with age. Urinary iron excretion in response to deferoxamine increased with age, with no obvious difference between splenectomized and nonsplenectomized patients. The ability to achieve iron balance with a daily dose of 20 mg/kg of deferoxamine was a function of the transfusion requirement splenectomized patients with lower blood requirements generally achieved negative iron balance, whereas nonsplenectomized patients did not. We conclude that the spleen should be removed when the transfusion requirement exceeds 250 ml/kg/year, which usually occurs between 6 and 8 years of age. In young patients with intact spleens, a higher dose of deferoxamine may be use in order to prevent hemosiderosis.

Adolescent↗
PubMed1993

Liver biopsy diagnosis of homozygous hemochromatosis: a diagnostic algorithm.

The diagnosis of homozygous hemochromatosis (HH) should be based on appropriate findings on liver biopsy specimens. In cases with equivocal morphologic features, quantitative tissue iron determination and calculation of the hepatic iron index generally enable one to distinguish HH from other types of hepatic iron overload. In this article, we describe a diagnostic algorithm that is designed to avoid diagnostic errors because of histologic misinterpretation or erroneous, usually false-negative, chemical iron studies. The algorithm also delineates a cost-effective method of using quantitative tissue iron analysis. Diagnostic biopsy features of uncomplicated HH include (1) hemosiderosis that involves primarily hepatocytes, with or without inactive cirrhosis, and (2) a tissue iron index of 1.9 or higher. Findings such as prominent fatty changes or lymphocytic piecemeal necrosis indicate the presence of HH in conjunction with another complicating condition or secondary iron overload in the absence of HH.

Algorithms↗
PubMed2002

New approaches to hematopoietic cell transplantation for hematological diseases in children.

Hematopoietic cell transplantation (HCT) has been used for more 30 years for the treatment of selected malignant and nonmalignant diseases. Traditionally, HCT for hematological disorders has relied on myeloablative conditioning before HLA-identical sibling bone marrow transplantation to correct the underlying hematological defect. Most children with hematological diseases who are referred to HCT have features that portend significant morbidity and early mortality. Among SAA patients who have HLA-identical sibling donors, younger patients with profound pancytopenia might be considered early for HCT. For others who lack sibling donors, patients who receive HCT from alternate sources have generally failed one or more courses of intensive immunosuppressive therapy and remain transfusion-dependent, some with hemosiderosis, red cell alloimmunization, and platelet transfusion refractoriness [44,46,48]. Currently, HCT for SCD is generally restricted to those who have experienced a significant sickle-related complication such as stroke, recurrent acute chest syndrome, or recurrent painful episodes [7,13]. In contrast, most reserve HCT in thalassemia for younger, Lucarelli class I, good-risk patients who have HLA-identical sibling donors, and veer away from older, high-risk thalassemics for whom transplantation is a riskier clinical intervention. For groups such as young adults with thalassemia major, HCT might become more widely applicable if its toxicity was reduced. Several approaches undergoing development include reduced-intensity conditioning and attempts to prevent GVHD. New methods to reduce the intensity and toxicity of conditioning as well as to use highly purified stem cells with the reduction in graft versus host disease may allow for the use of matched unrelated donors or haploidentical donors. This would serve to provide potentially more children who could benefit from stem cell transplantation with donors. These advances will hopefully lead to benefits for the majority of children who lack HLA-identical donors.

Adolescent↗
PubMedDate not supplied

Vitreous Hemorrhage.

The incidence of spontaneous vitreous hemorrhage is approximately 7 cases per 100,000 population. Proliferative diabetic retinopathy (32%), retinal tear (30%), proliferative retinopathy after retinal vein occlusion (11%) and posterior vitreous detachment without retinal tear (8%) are the most common causes of spontaneous vitreous hemorrhage. Vitreous hemorrhage can be caused by the pathologic mechanisms of disruption of normal retinal vessels, bleeding from diseased retinal vessels or abnormal new vessels, and extension of hemorrhage through the retina from other sources. Hemorrhage into the vitreous gel results in rapid clot formation and is followed by slow clearance of approximately 1% per day. The cellular response to vitreous hemorrhage is unusual with regard to hemorrhage in any tissue outside the vitreous cavity and has been compared to a "low-turnover" granuloma. Unique clinicopathologic features of long-standing vitreous hemorrhage include cholesterolosis bulbi (synchysis scintillans), hemoglobin spherulosis, and vitreous cylinders. Complications of nonclearing vitreous hemorrhage are hemosiderosis bulbi and glaucoma. Ghost cell glaucoma, hemolytic glaucoma, and hemosiderotic glaucoma may result from vitreous hemorrhage. The established treatment option for nonclearing vitreous hemorrhage is pars plana vitrectomy. Experimental nonsurgical treatment options involve improvement of physiologic clearance mechanisms in order to accelerate fibrinolysis, liquefaction, hemolysis and phagocytosis.

Animals↗
PubMed1976

Cardiac pathologic findings in patients treated with bone marrow transplantation.

Cardiac pathologic findings were analyzed in 22 necropsy cases from a series of 29 patients with leukemia, aplastic anemia, or metastatic cancer who had been treated with ablative therapy followed by bone marrow transplantation. Some cardiac alterations were similar to those that occur in patients with hematologic and neoplastic diseases not treated with bone marrow transplantation, and consisted of cardiomegaly, cardiac atrophy, hemorrhage, foci of necrosis due to shock associated with sepsis or hepatic failure, myocardial abscesses secondary to systemic candidiasis or staphylococcal infection, fibrinous pericarditis, and hemosiderosis. Other cardiac alterations were more specifically related to factors associated with transplantation procedure. Six patients exhibited a distinctive interstitial reactive change characterized by the presence of (1) moderate to large numbers of Anitschkow cells, occurring alone or in small cellular aggregates and histiocytes, histiocytic cells with nuclei of the Anitschkow type, lymphoid cells, and plasma cells, and (2) nuclei of the Anitschkow type in cardiac vascular and endocardial smooth muscle, endothelial and Schwann cells, and occasional cardiac muscle cells. This alteration may have been induced by abnormal immune mechanisms, as suggested by the observation that five of the six patients with interstitial change had clinical evidence of graft-versus-host disease. Two patients developed fatal congestive cardiac failure in the early post-transplant period and exhibited myocardial damage with histologic and post-transplant period features indicative of severe acute injury. Findings in these two patients consisted of necrotic muscle cells, which exhibited multiple contraction bands, diastase-resistant PAS staining, and intracellular fibrin deposits; microthrombi, which were composed of fibrin and occasionally of fibrin and platelets; and extravasated erythrocytes and fibrin strands in the interstitium. One of the two patients also exhibited unusual nuclear alterations, which were characterized by replacement of normal chromatin by palely stained fibrous and filamentous material. Clinicopathologic analysis strongly suggested that the fatal cardiotoxicity in both patients resulted primarily from effects of high doses of cyclophosphamide, which were administered as part of a four drug regimen that provided tumor ablation and immunosuppression for bone marrow transplantation. Our findings emphasize the need for less toxic antineoplastic and immunosuppressive therapy for use in bone marrow transplantation procedures.

Abscess↗
PubMed1996

Renal cryoablation in a canine model.

OBJECTIVES: To assess the potential safety and utility of cryoablation for treatment of selected renal tumors in a canine model. METHODS: Ultrasound and direct physical measurements (depth and width) of five cryolesions were compared. Cryolesions were examined histologically in 6 animals, which were killed at 4 hours, 2 days, 1 week, 3 weeks, 6 weeks, and 12 weeks. Mortality/morbidity was assessed in 12 animals over a 1-month interval, where 6 animals received small (approximately 2 cm) cryolesions and 6 animals received large (one third to one half of kidney) cryolesions. Laparoscopic cryoablation was performed in 2 animals. RESULTS: A statistically significant association of physical and ultrasound dimensions was observed (correlation coefficient R = 0.9295; P = 0.0001). Histologic studies in animals killed up to 1 week after cryoablation revealed complete coagulative necrosis within the cryolesion. The boundary transition from normal to complete tissue necrosis occurred in 1 to 2 mm. Animals killed 3 weeks to 3 months after cryoablation revealed progressive organization with granulation tissue, chronic inflammation, hemosiderosis, fibrosis, and contraction of the cryolesion with parenchymal loss. Untreated renal tissue was histologically normal in all kidneys. No mortality or morbidity was detected in the 12 animals followed for 30 days regardless of the size of the cryolesion. Laparoscopic cryoablation was performed successfully in 2 animals without modification of standard laparoscopic methods. CONCLUSIONS: Sonographic, histologic, and laparoscopic data in a canine model suggest that cryoablation may be a safe, feasible, and useful method for treatment of selected renal neoplasms.

Animals↗
PubMed2002

Biotransformation, genotoxic, and histopathological effects of environmental contaminants in European eel (Anguilla anguilla L.).

A prolonged toxicity study was carried out in young European eel (Anguilla anguilla L.) to evaluate the effects of environmental contaminants, namely, two individual standard compounds, benzo[a]pyrene (BaP) and dehydroabietic acid (DHAA), and a complex mixture, bleached kraft pulp mill effluent (BKPME). Fish were exposed to BaP (0.22, 0.45, and 0.9 microM) and BKPME (3.12%, 6.25%, and 12.5% (v/v)) for 3, 7, and 30 days and to DHAA (0.07, 0.15, and 0.30 microM) for 3, 7, 30, 90, and 180 days. The biomarkers include biotransformation and genotoxicity indicators, such as total ethoxyresorufin O-deethylase (EROD) activity and frequency of erythrocytic nuclear abnormalities (ENAs), respectively. Hematological dynamics was assessed as frequency of immature erythrocytes (IEs). Histopathological examinations were carried out for the highest concentrations and for 30 days and longer exposures. Total EROD increases significantly only after 180 days of DHAA exposure. However, significant ENA induction was generally observed during exposure to all contaminants tested. Nevertheless, some of the ENA results suggest an altered genotoxic response, which may arise either from short-term exposures to the highest contaminant levels or long-term exposures to the lowest contaminant levels. IE frequency decreased significantly after 30 days of exposure to 0.45 microM BaP and 180 days of exposure to the entire DHAA concentration range. Increased density of pigmented macrophage aggregates in 30-day BaP- and BKPME-exposed fish as well as in 90- and 180-day DHAA-exposed fish confirmed histopathological liver alterations. Bile accumulation in hepatocytes after BaP treatment, cytoplasmic vacuolization and cell atrophy following DHAA exposure, as well as liver loss of parenchymal cells in BKPME-exposed fish, were also detected. Dispersed necrosis and focal inflammation were observed in the livers of all treated groups. Fish exposed to DHAA and BKPME showed skin and gill disruption as well as kidney Malpighian corpuscle alterations. All 30-day-treated groups revealed intense spleen hemosiderosis, indicating increased erythrophagia. This splenic effect may be strongly correlated with the observed disappearance of ENAs. Neoplastic lesions were not found. A multibiomarker strategy, which includes EROD, ENA, and IE assays as well as histopathological studies, contributed to a better understanding of the global toxic process.

Abietanes↗