Updated toxicological profile for mercury.
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Adult↗
Biomedical subjects
D E Jones
Publications and source records attributed to D E Jones.
Summary report for the expert panel review of the toxicological profile for mercury.
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Animals↗
Age-related differences in global-local processing: stability of laterality differences but disproportionate impairment in global processing.
Visual processing of global and local features differentially engages the right and left hemispheres and requires different allocations of spatial attention. To further understand the decline in visual cognition and visual attention with age, we studied the performance of healthy young subjects and healthy elders on a global-local figures task. The results showed that elders processed global images more quickly when presented in the left visual field and local images in the right visual field, similarly to the young controls. However, we did observe a significant impairment in the elders' ability to process global figures compared with local figures, despite there being no overall difference between global and local processing speed among the young. It is thought that this age-related decline in global processing is related to the narrowed attentional field that can be demonstrated in other age-related visual processing declines such as visual search and useful field of view.
Adult↗
Host susceptibility factors to cutaneous leishmaniasis.
The host-pathogen relationship is the focus of many different studies which use a variety of disease models and different pathogens. Immunological studies in the mouse using the intracellular parasite Leishmania have helped define several aspects of host-pathogen interactions. Resistance to Leishmania is dependent on the development of CD4+ Th1 cells which promote an effective cell mediated immune response. Production of the cytokine IFN-gamma during this immune response activates macrophages enabling them to kill the parasite and control the infection. In contrast, susceptibility to this parasite is characterized by a Th2 response which produces predominantly IL-4. This cytokine promotes high antibody titers directed towards the parasite but does not activate macrophages for parasite killing. This host response results in high parasite numbers and a progressive increase in lesion size. The mouse model of leishmaniasis has been extremely useful in gaining an understanding of the immunological factors important in determining T cell commitment into Th1 or Th2 populations during an in vivo immune response.
Animals↗
Inhibition of transcription of the human c-myc protooncogene by intermolecular triplex.
Triplex-forming oligonucleotides (TFOs) have been shown to inhibit both transcription in vitro and the expression of target genes in cell culture by binding to polypurine/polypyrimidine sequences in several human gene promoters. The c-myc protooncogene is overexpressed in a variety of human cancers and appears to play an important role in the proliferation of these cells. In an attempt to assay the ability of triplex-forming oligonucleotides to inhibit expression of a target gene in vivo, we have developed a cellular system involving transfection of a c-myc promoter-driven luciferase reporter plasmid with triplex-forming oligonucleotides targeted to the human c-myc protooncogene. To increase the stability of the TFO, we have used modified phosphorothioate oligonucleotides. Triplex formation with a modified phosphorothioate oligonucleotide occurs with approximately equal binding affinity as that seen using a phosphodiester oligonucleotide. Phosphorothioate-modified TFOs targeted to c-myc inhibit transcription of the c-myc promoter in HeLa cells as demonstrated by a decrease in luciferase expression from a luciferase reporter gene construct. These results suggests that triplex formation may represent a gene-specific means of inhibiting specific protooncogene expression.
Base Sequence↗
No evidence for involvement of the interleukin-10 -592 promoter polymorphism in genetic susceptibility to primary biliary cirrhosis.
BACKGROUND/AIMS: Primary biliary cirrhosis is a chronic cholestatic liver disease with an autoimmune aetiology. Family studies, which have shown a significantly increased incidence of primary biliary cirrhosis in the close relatives of patients, suggest that genetic factors play a significant role in determining disease susceptibility. Several studies have previously identified loci which appear to play a role in determining this susceptibility, including the MHC class II allele HLA DR8, and the class III encoded C4A null allele (C4AQ0). Here, we have studied another candidate susceptibility locus in primary biliary cirrhosis, an apparently functional biallelic polymorphism at position -592 in the promoter region of the gene encoding the immuno-modulatory cytokine interleukin-10. Interleukin-10 plays an important role in the functional control, in vivo, of autoreactive Th-1 type CD4+ T-cells, with experimental manipulation of interleukin-10 leading to significant modulation of disease development in animal models of autoimmunity. METHODS: Interleukin-10 -592 genotypes were studied by polymerase chain reaction in 171 well-characterised, histologically-staged, primary biliary cirrhosis patients and 141 locally matched controls. RESULTS: Of 171 primary biliary cirrhosis patients, 99 were homozygous for the commoner allele (C/C), 68/171 (40%) were heterozygotes (A/C), whilst 4/171 (2%) were homozygous for the rarer allele (A/A). These genotype frequencies were not significantly different from those seen in controls (p=0.49, odds ratio 1.2 [0.8-1.91). CONCLUSIONS: These findings, in the first study of IL-10 as a candidate locus in a human autoimmune disease, suggest that IL-10 -592 is not a susceptibility locus in primary biliary cirrhosis.
Autoimmune Diseases↗
Primary biliary cirrhosis: clinical and associated autoimmune features and natural history.
Primary biliary cirrhosis, a chronic liver disease, predominately affects middle-aged women. The diagnosis is established by the presence of disease-specific autoantibodies and compatible liver histology showing focal immune-mediated damage to the intrahepatic bile ducts. Patients now are detected prior to the onset of symptoms typical of cholestasis with abnormal liver function tests, or even prior to the onset of abnormal liver function tests, with positive antimitochondrial antibodies. Earlier diagnosis is changing not only our appreciation of the prevalence of this condition, but also of the natural history. The disease appears to be heterogeneous with some patients having a slow progression and a normal life-expectancy, although other patients have a more aggressive course developing symptoms and end-stage disease that leads to death or liver transplantation.
Autoimmunity↗
Advanced practice nursing in the Nordic countries.
Changes in the delivery of health care and changes in population characteristics and health care requirements mandate changing requirements in nursing education. This is necessary to meet patient and family needs and to deliver quality health care. This paper describes the background to nursing education in the Nordic countries and gives an account of an initiative in Norway to prepare advanced practice nurses for clinical practice in this dynamic environment.
Curriculum↗
Painless small bowel ischemia presenting with diarrhea and weight loss.
Chronic ischemia of the small bowel is classically described as presenting with abdominal pain associated with eating (intestinal angina). Here we describe the cases of two patients with chronic small bowel ischemia who presented atypically with painless watery diarrhea and weight loss. These cases suggest that the clinical spectrum of chronic small bowel ischemia may be wider than previously appreciated. Chronic ischemia of the small bowel should be included in the differential diagnosis for painless watery diarrhea in the context of weight loss.
Aged↗
Enteric beta-defensin: molecular cloning and characterization of a gene with inducible intestinal epithelial cell expression associated with Cryptosporidium parvum infection.
A growing body of evidence suggests that endogenous antibiotics contribute to the innate defense of mammalian mucosal surfaces. In the cow, beta-defensins constitute a large family of antibiotic peptides whose members have been previously isolated from the respiratory and oral mucosa, as well as circulating phagocytic cells. A novel bovine genomic clone with beta-defensin-related sequence [corrected] related to those of these alpha-defensins was isolated and characterized. The corresponding cDNA was isolated from a small intestinal library; its open reading frame predicts a deduced sequence of a novel beta-defensin, which we designate enteric beta-defensin (EBD). Northern blot analysis of a variety of bovine tissues revealed that EBD mRNA is highly expressed in the distal small intestine and colon, anatomic locations distinct from those for previously characterized beta-defensins. EBD mRNA was further localized by in situ hybridization to epithelial cells of the colon and small intestinal crypts. Infection of two calves with the intestinal parasite Cryptosporidium parvum induced 5- and 10-fold increases above control levels of EBD mRNA in intestinal tissues. An anchored-PCR strategy was used to identify other beta-defensin mRNAs expressed in the intestine. In addition to that of EBD, several low-abundance cDNAs which corresponded to other beta-defensin mRNAs were cloned. Most of these clones encoded previously characterized beta-defensins or closely related isoforms, but two encoded a previously uncharacterized prepro-beta-defensin. Northern blot evidence supported that all of these other beta-defensin genes are expressed at levels lower than that of the EBD gene in enteric tissue. Furthermore, some of these beta-defensin mRNAs were abundant in bone marrow, suggesting that in enteric tissue their expression may be in cells of hematopoietic origin. Extracts of small intestinal mucosa obtained from healthy cows have numerous active chromatographic fractions as determined by an antibacterial assay, and one peptide was partially purified. The peptide corresponded to one of the low-abundance cDNAs. This study provides evidence of beta-defensin expression in enteric tissue and that the mRNA encoding a major beta-defensin of enteric tissue, EBD, is inducibly expressed in enteric epithelial cells. These findings support the proposal that beta-defensins may contribute to host defense of enteric mucosa.
Amino Acid Sequence↗
Public health implications of environmental exposures.
The Agency for Toxic Substances and Disease Registry (ATSDR) is a public health agency with responsibility for assessing the public health implications associated with uncontrolled releases of hazardous substances into the environment. The biological effects of low-level exposures are a primary concern in these assessments. One of the tools used by the agency for this purpose is the risk assessment paradigm originally outlined and described by the National Academy of Science in 1983. Because of its design and inherent concepts, risk assessment has been variously employed by a number of environmental and public health agencies and programs as a means to organize information, as a decision support tool, and as a working hypothesis for biologically based inference and extrapolation. Risk assessment has also been the subject of significant critical review. The ATSDR recognizes the utility of both the qualitative and quantitative conclusions provided by traditional risk assessment, but the agency uses such estimates only in the broader context of professional judgment, internal and external peer review, and extensive public review and comment. This multifaceted approach is consistent with the Council on Environmental Quality's description and use of risk analysis as an organizing construct based on sound biomedical and other scientific judgment in concert with risk assessment to define plausible exposure ranges of concern rather than a single numerical estimate that may convey an artificial sense of precision. In this approach biomedical opinion, host factors, mechanistic interpretation, molecular epidemiology, and actual exposure conditions are all critically important in evaluating the significance of environmental exposure to hazardous substances. As such, the ATSDR risk analysis approach is a multidimensional endeavor encompassing not only the components of risk assessment but also the principles of biomedical judgment, risk management, and risk communication. Within this framework of risk analysis, the ATSDR may rely on one or more of a number of interrelated principles and approaches to screen, organize information, set priorities, make decisions, and define future research needs and directions.
Adaptation, Physiological↗
Interferon-gamma and interleukin 4 gene expression in cows infected with Mycobacterium paratuberculosis.
OBJECTIVE: To determine whether clinical progression of paratuberculosis in cattle was associated with alterations in cytokine gene expression in affected tissues. ANIMALS: 5 uninfected adult Holstein cows, 7 adult Holstein cows naturally infected with Mycobacterium paratuberculosis that did not have clinical signs of disease, and 4 adult Holstein cows naturally infected with M paratuberculosis that had progressive clinical signs of infection. PROCEDURE: Samples of ileum and cecal lymph nodes were obtained from each animal at the time of slaughter. A reverse transcriptase-competitive polymerase chain reaction assay was used to determine mRNA expression of interferon-gamma (IFN-gamma) and interleukin 4 in each sample. RESULTS: Interferon-gamma gene expression was significantly higher in ileum and cecal lymph node samples from subclinically infected cows than from clinically infected cows. CONCLUSIONS AND CLINICAL RELEVANCE: Progression of paratuberculosis to clinical stages is associated with reduced expression of IFN-gamma at site of infection. If immune response to M paratuberculosis can be manipulated so that IFN-gamma expression is increased, resistance to infection in cattle might be enhanced.
Animals↗
Leishmania major-infected C3H mice treated with anti-IL-12 mAb develop but do not maintain a Th2 response.
Leishmania major-infected C3H mice develop a Th1 response, but studies have shown that treatment of C3H mice with anti-IL-12 or anti-IFN-gamma mAb promotes the development of a Th2 response and susceptibility. However, we discovered that C3H mice treated for 3 wk with either anti-IL-12 or anti-IFN-gamma mAb eventually resolved their lesions and switched from a Th2 to a Th1 response. No significant differences in IL-4, IL-10, or IFN-gamma levels or in the parasite burden could be detected between BALB/c and anti-IL-12-treated C3H mice early after infection, suggesting that the instability of the Th2 response in anti-IL-12-treated C3H mice was unrelated to levels of these cytokines and parasite numbers. However, anti-IL-12-treated C3H mice continued to produce IL-12 in spite of exhibiting a Th2 phenotype. To determine whether the production of IL-12 was associated with the healing observed in these animals, we treated C3H mice with anti-IL-12 continuously for 12 wk. In contrast to C3H mice given anti-IL-12 for 3 wk, C3H mice continuously treated with anti-IL-12 failed to heal. These results suggest that qualitative differences in Th2-type responses may influence their stability and that the presence of IL-4, IL-10, or high parasite numbers is not sufficient to maintain a Th2 response in mice with certain genetic backgrounds.
Animals↗
Primary angioplasty reduces risk of myocardial rupture compared to thrombolysis for acute myocardial infarction.
Although the mechanical complications of acute ventricular septal defect and acute mitral regurgitation are uncommon after acute myocardial infarction, these complications are associated with an extremely high morbidity and mortality. We hypothesized that the administration of thrombolytic drugs may result in hemorrhagic infarction as well as the potential for incomplete revascularization and thus may lead to an increased incidence of mechanical complications compared to primary angioplasty. Accordingly, we reviewed the data of the most contemporary thrombolytic and primary angioplasty trials and compared the incidence of mechanical complications among 36,303 patients treated with thrombolytics reported in the GUSTO trial to the incidence of mechanical complications among 1,295 patients treated with primary angioplasty obtained from the PAMI-1 and PAMI-2 trials. We found that angioplasty resulted in an overall 86% relative risk reduction in mechanical complications (2.20% vs. 0.31%, P < 0.001). In comparison to thrombolytic therapy, angioplasty resulted in an 82% decrease in acute mitral regurgitation (1.73% vs. 0.31%, P < 0.001) and a 100% decrease in acute ventricular septal defect (0.47% vs. 0.00%, P < 0.03). In conclusion, in patients with acute myocardial infarction, reperfusion with primary angioplasty is associated with less myocardial rupture and mechanical complications than thrombolytics. This finding may, in part, explain the improved prognosis observed in myocardial infarction patients treated with primary angioplasty.
Adult↗
Hepatocellular carcinoma in primary biliary cirrhosis and its impact on outcomes.
In this study we have determined the incidence of hepatocellular carcinoma (HCC) development in primary biliary cirrhosis (PBC) and its effects on patient survival. Six hundred and sixty seven patients with liver histology compatible with or diagnostic of PBC were seen over a 20-year period. Two hundred and seventy three patients who had stage III or IV disease on their last biopsy and who had been followed up for at least 1 year following that biopsy (total follow-up with advanced disease 2,010 patient years) were identified (243 female, 30 male). Patients who developed HCC were identified and their confounding risk factors were excluded. Mayo risk scores were calculated for each clinic attendance and expected survival for each time point was compared with subsequent actual survival. Sixteen cases of HCC were seen in the patients with stage III or IV disease on last biopsy, providing an overall incidence of 5.9% in this group. Fourteen of these patients had died of HCC related causes, and 2 patients were alive at the census point. The incidence of HCC was significantly higher in males with stage III/IV disease than in females (20% vs. 4.1%, P < .005). Nine of one hundred and eight (8.3%) total female deaths in this group was attributable to HCC compared with 5 of 11 (45.5%, P < .05) male deaths. HCC was not seen in any of the 394 patients with stage I and II PBC followed-up over the same time period. Throughout the disease course of all PBC patients with HCC, the Mayo prognostic model over-predicted survival. Whereas it is a relatively rare complication of cirrhotic PBC in women, HCC is a relatively common cause of death in male PBC patients with cirrhosis. HCC typically develops several years after the onset of cirrhosis, and is poorly predicted by prognostic models. In view of these findings, consideration should be given to careful screening for HCC in male PBC patients with cirrhosis. The risk of HCC development may be an additional reason to consider earlier transplantation in these patients.
Aged↗
T cell responses to natural human proteins in primary biliary cirrhosis.
The study of T cell responses to autoantigens in human autoimmunity has been hampered by difficulties, firstly in identifying significant autoantigens, and secondly in the purification of authentic human proteins in sufficient quantities to allow characterization of antigen-specific T cell responses. In this study we have purified a human autoantigen, pyruvate dehydrogenase, retaining its enzymatic activity, and characterized autoreactive T cell responses to it in a human autoimmune disease, primary biliary cirrhosis. T cell responses to a mixture of the E2 and protein X subunits of human pyruvate dehydrogenase complex are seen in most affected patients, but in only a small minority of normal and chronic liver disease controls. By contrast, responses to whole pyruvate dehydrogenase complex occur with equal frequency in both groups. This suggests that responses to the E2 component/protein X of pyruvate dehydrogenase complex play a role in the pathogenesis of primary biliary cirrhosis. The availability of significant quantities of the human autoantigen in primary biliary cirrhosis makes this condition an interesting model in which to study true autoreactive human T cell responses.
Adult↗
Primary biliary cirrhosis.
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Autoimmune Diseases↗
Biochemistry and autoimmune response to the 2-oxoacid dehydrogenase complexes in primary biliary cirrhosis.
Pyruvate dehydrogenase complex (PDC), 2-oxo-glutarate dehydrogenase complex (OGDC), and the branched-chain 2-oxoacid dehydrogenase complex (BCOADC) constitute the 2-oxoacid dehydrogenase family of multienzyme complexes. These complexes, which are larger than ribosomes and which consist of multiple copies of E1, E2, and E3 subunits together with regulatory kinases and phosphatases and, in the case of PDC, an E3-binding protein (protein X), each play an important role in oxidative metabolism in mitochondria. Primary biliary cirrhosis (PBC) is associated with a high incidence of autoantibodies directed at mitochondrial autoantigens (the antimito-chondrial antibodies), identified as the E2 components of PDC, OGDC, and BCOADC, together with protein X and the E1 alpha and E1 beta subunits of PDC. The dominant B-cell autoepitope in PBC has been identified as the inner lipoic acid binding domain of PDC-E2, with the lipoic acid co-factor, which plays a critical role in E2 enzymatic activity, playing a role in autoantibody binding to antigen. Autoreactive CD4+ T cells specific for human PDC-E2 are also present in both the peripheral blood and liver mononuclear cell infiltrates of PBC patients. The mechanism of break-down of B-cell and T-cell self-tolerance to these ubiquitous mitochondrial antigens in such an organ-specific manner remains unclear. The apparent importance of autoreactive responses to these self-antigens does, however, raise the possibility that antigen-specific immunotherapy may offer a novel route to therapy in PBC.
3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide)↗