Dose-dependent liver tissue repair in chloroform plus thioacetamide acute hepatotoxicity

The objective of this study was to test whether a binary mixture (BM) of chloroform (CHCl(3)) and thioacetamide (TA) causes a dose-dependent liver injury and an opposing tissue repair. Liver injury was assessed by plasma alanine aminotransferase (ALT) and histopathology. Tissue repair was measured by [(3)H-CH(3)]-thymidine ((3)H-T) incorporation into hepatonuclear DNA and PCNA over a time course of 0-72h. Male Sprague-Dawley (S-D) rats received six- and five-fold dose ranges of TA and CHCl(3), respectively. ALT levels and (3)H-T incorporation were in complete agreement with corresponding microscopic observations, and only ALT elevation and (3)H-T incorporation data are presented here. Liver injury observed after exposure to BM was no different than addition of injuries caused by individual compounds. Tissue repair was prompt and adequate, leading to recovery from injury and animal survival. Tissue repair is dose-dependent and plays central role in the hepatotoxic outcome.     

Toxicity assessment of complex mixtures remains a goal

One of the initial steps in remediating contaminated environments is to assess the human and ecological health risk associated with exposure to contaminants in a specific medium. Presented here are the results of a five-year study investigating the toxicity of simple and complex mixtures. A series of model compounds and simple mixtures including polycyclic aromatic hydrocarbons (PAHs), pentachlorophenol (PCP), and halogenated aliphatic hydrocarbons (HAHs) were analyzed. Mixture toxicity was studied using microbial genotoxicity assays and cytotoxicity assays with renal and neural cells. The majority of binary mixtures described here induced additive responses. A limited number of samples were identified where binary mixtures induced inhibitory effects. For example, benzo(a)pyrene (BAP) alone induced 30% renal cell death, whereas an equimolar dose of chrysene and BAP only produced 1.6% cellular death. In none of the mixtures tested did the mixture toxicity results deviate from the predicted results by an order of magnitude. The results from testing binary mixtures in this study indicate that the results did not deviate significantly from additivity. Complex mixture results were more difficult to interpret. The toxicity of complex mixtures could not be accurately predicted based on chemical analysis. This could be due to chemical interactions or due to the presence of unidentified chemicals, such as alkyl PAHs or high molecular weight PAHs that are not included in the standard risk assessment procedure. Even though the results from these in vitro studies indicate that additive assumptions will generally be appropriate for binary mixtures similar to the ones tested here, the risk associated with complex mixtures remains a challenge to predict. Before the results of toxicity testing can be used to adjust risk assessment calculations, it is important to fully appreciate the chemical composition and to understand the mechanism of observed chemical interactions in animals chronically exposed to low doses of chemical mixtures. This research was supported by ATSDR Grant no. ATU684505 and NIEHS SBRP Grant no. P42 ES04917.     

Akt: a potential target for thyroid cancer therapy

Thyroid cancer is a heterogeneous disorder characterized by gene mutations that activate signaling pathways, and also by abnormalities in tumor suppressor genes and cell cycle proteins. Activation of the Akt/PKB signaling pathway appears to be an important event in thyroid tumorigenesis and, perhaps, in tumor progression too. Akt is activated in Cowden's syndrome through inactivation of PTEN, a negative regulator of Akt. Cowden's syndrome is an autosomal dominant multiorgan hamartoma syndrome characterized by benign and malignant thyroid tumors, breast cancers, and colon cancers. In addition, the Akt pathway appears to be activated in a significant proportion of sporadic thyroid cancers through activation of growth factor pathways by thyroid oncogenes and/or receptor overexpression. Disruption of PI3-kinase activity pharmacologically or disruption of Akt signaling using dominant negative cDNA expression have demonstrated salutary effects on several cancer models in vitro. Therefore, Akt represents an attractive target for pharmaceutical development for a variety of malignancies, including thyroid cancer.     

Multisequence magnetic resonance imaging study of neuropsychiatric systemic lupus erythematosus

OBJECTIVE: To investigate the relationship between magnetization transfer imaging (MTI), diffusion-weighted imaging (DWI), proton magnetic resonance spectroscopy (H-MRS), and T2 relaxometry findings in patients with primary neuropsychiatric systemic lupus erythematosus (NPSLE). METHODS: The study group consisted of 24 female patients (mean age 36 years [range 23-65]) who had had a variety of neuropsychiatric symptoms that were judged to be due to NPSLE according to the criteria of the American College of Rheumatology. Patients with current active disease were excluded from participation. Quantitative MTI, DWI, H-MRS, and T2 relaxometry data were acquired in all patients, and the correlation coefficients were calculated. RESULTS: MTI results reflecting a decrease in homogeneity of cerebral parenchyma correlated significantly with H-MRS results representing axonal damage. MTI results also correlated significantly with DWI results reflecting increased diffusivity in the cerebral parenchyma. Finally, MTI results reflecting decreased cerebral homogeneity correlated significantly with increased T2 relaxation time, associated with either edema or gliosis. Increased T2 relaxation time correlated significantly with DWI results reflecting increased diffusivity. With the exception of the correlation between H-MRS and MTI findings, there was no significant correlation between H-MRS results and any other parameter. CONCLUSION: The selected study parameters represent different biologic features in the human brain and can be informative with regard to different pathologic processes in NPSLE. The demonstrated associations between MTI, DWI, H-MRS, and T2 data in patients with a history of NPSLE suggest that there is one pathogenesis and/or common neuropathologic outcome in NPSLE despite differences in clinical presentation.     

Remicade as TNF suppressor in patients with myelodysplastic syndromes

Remicade, a chimeric human-murine monoclonal antibody capable of neutralizing tumor necrosis factor alpha was given to 37 low-risk myelodysplastic syndromes (MDS) patients in two cohorts; 5 and 10 mg/kg intravenously every 4 weeks for 4 cycles. Median age was 68 years, 33 had primary MDS, 14 had refractory anemia (RA), 14 RA with ringed sideroblasts, 9 RA with excess blasts. Nine patients stopped therapy prior to completing 4 cycles, 3 from cohort 1 and 6 from cohort 2 and response was evaluated using the International Working Group criteria in 28 patients who completed the 4 cycles. Six patients showed disease progression, 14 had stable disease and 8 showed hematologic responses, 3/15 (20%) in cohort 1 and 5/13 (38%) in cohort 2. Two patients had multi-lineage responses, 2 had > 100% increase in absolute neutrophils, 1 had > 1 gm/dl increase in hemoglobin, 1 had reduction in blasts from 7% to 1%, and 2 had minor cytogenetic responses (> 50% reduction in + 8 and 20q-metaphases respectively). We conclude that Remicade may have a variety of activities in low risk MDS patients, is well tolerated with a high patient compliance, and may be considered for combination therapy in the future.     

Imported malaria in Kuwait (1985-2000)

BACKGROUND: The objective of this study was to document the status of malaria infection and effect of preventive measures on the epidemiologic profile of imported malaria cases in Kuwait during 1985-2000. METHODS: The study included screening of two groups of individuals for malaria infection by microscopy; (1) all migrant workers from malaria-endemic countries on their first entry to Kuwait; and (2) all suspected malaria cases already residing in the country. The study period was divided into pre-war (1985-1990), postwar (1992-1997) and proactive preventive (1998-2000) periods. During the proactive preventive period, the home countries were also involved in screening for malaria infection in all prospective immigrants to Kuwait. RESULTS: The annual incidence of malaria cases detected during the pre-war, postwar and proactive preventive periods ranged between 465 and 1,229, 654 and 1,379, and 248 and 393, respectively. Plasmodium vivax infection was detected in 71% of the cases and P. falciparum in 27%. The number of malaria cases detected increased to >1,300 after the war during 1992-1993. However, the number of malaria cases dropped significantly to less than 400 during 1998-2000 (p80%) of malaria patients were young male adults between 21 and 40 years of age. The data on drug resistance were not well defined, due to limited testing. CONCLUSION: This study suggests that the proactive preventive program to screen all prospective immigrants for malaria infection in their home countries significantly reduced the numbers of imported infections to <400 cases/year, a drop of 52.6%. In addition, it also identified a group of settled immigrants, the majority of whom were at high risk for acquisition of malaria infection during their visit to home countries. There is an urgent need to target this group for prevention strategies such as education/information and other preventive measures against malaria infection.     

Neurotoxicity of polycyclic aromatic hydrocarbons and simple chemical mixtures

Polycyclic aromatic hydrocarbons (PAHs) are a major class of environmental pollutants. These chemicals are the products of incomplete combustion and are present in every compartment of the environment. While the carcinogenic potential of these chemicals has been investigated in numerous studies, very little is known about the potential of these chemicals to produce damage to neural cells. The objective of this study was to investigate the toxicity of several model PAHs and binary mixtures of these chemicals in neural cells. Chemicals tested included benzo[a]pyrene (BaP), chrysene, anthracene, and pentachlorophenol (PCP). Four end points, including amino acid incorporation, total protein, total cell count, and viable cells (trypan dye exclusion), were measured in SY5Y human neuroblastoma cells and C6 rat glioma cells. The most sensitive measure of PAH toxicity in neural cells was amino acid incorporation into proteins. BaP was the most toxic of all PAHs tested, and anthracene failed to produce a toxic response at any concentration tested. Without metabolic activation, BaP induced a significant cytotoxic response at a concentration of 30 microM. With activation (0.25% S9), BaP induced a response at concentration levels of 3 microM and 30 microM. Minimal toxicity was observed with chrysene at the highest concentration tested, and anthracene failed to produce a toxic response at any concentration tested. With mixtures of PAHs the majority of samples induced additive responses. The minimum concentration required to induce a significant response was reduced for the mixture of chrysene and BaP when compared to BaP alone. In addition, PCP appeared to increase the inhibition of acetylcholinesterase by mipafox. The data suggest that PAHs are capable of producing damage to neural cells only at concentrations that are near their solubility limits.