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PubMed2002

(123)I- or (125)I-metaiodobenzylguanidine visualization of brown adipose tissue.

UNLABELLED: (123)I-Metaiodobenzylguanidine (MIBG) accumulations that do not correspond to any tumor are observed occasionally on the medial aspect of the upper back or shoulder of children. The true nature of such accumulations is unknown, and we hypothesized that they represent interscapular brown adipose tissue (IBAT) visualized by scintigraphy. METHODS: Wistar rats (7 wk old) received MIBG labeled with (123)I or (125)I. Autoradiography was performed, and concentrations of the tracer in the interscapular subcutaneous tissue were identified histopathologically. The effects of 6-hydroxydopamine, reserpine, and beta 3-adrenergic receptor agonist (CL316,243) on the accumulation were investigated to elucidate the mechanism of uptake into BAT. RESULTS: Autoradiography showed well-defined distinct accumulation in the subcutaneous tissue on the upper back, and hematoxylin-eosin and anti-uncoupling protein 1 antibody staining confirmed that it was BAT. The percentage injected dose per gram in BAT was as high as that in the heart and was quite different from the concentration in white adipose tissue. Preadministration of 6-hydroxydopamine or reserpine resulted in lower MIBG concentrations in BAT. Activation of the beta 3-adrenergic receptor accelerated the washout of MIBG in BAT and caused an increase in concentration in white adipose tissue. CONCLUSION: MIBG accumulates in the adrenergic nervous system in BAT, and IBAT is distinguished from the surrounding white adipose tissue. To our knowledge, BAT has not been visualized previously. We showed that MIBG scintigraphy might be suitable for the investigation of BAT and treatment of human obesity.

3-Iodobenzylguanidine↗
PubMed1986

Urosepsis.

Many years ago Osler suggested that "it is of use from time to time to take stock, so to speak, of our knowledge of a particular disease to see where we stand in regard to it, to inquire to what conclusions these accumulated facts seem to point, and to ascertain in what direction we may look for fruitful investigations in the future." With regard to gram-negative bacteremia, there is extant a notable and striking increase in both the incidence of these infections and the involvement of organisms that previously caused disease only uncommonly. Factors related to this escalation include an increase in the number of elderly and debilitated hospitalized patients, the large number of individuals with malignant disease who are immunosuppressed by their disease and the drugs used to treat them, the ubiquity of various types of respirators, drainage tubes, and catheters that may be colonized by gram-negative bacteria, and the progressively increasing resistance of these organisms to a growing number of antimicrobial agents. The emergence of resistance is at least partly due to the inappropriate use of antibiotics, often in combination, for prophylaxis or empiric therapy. It is unfortunate that even the necessary use of antibiotics will increase the frequency of disease caused by these gram-negative organisms. The inescapable conclusion is that gram-negative infections and bacteremia will only increase in prevalence in the future. Investigation of the pathophysiology of shock due to gram-negative sepsis has revealed that most of the physiologic alterations are mediated by products of the host's own immune system.(ABSTRACT TRUNCATED AT 250 WORDS)

Anti-Bacterial Agents↗
PubMedDate not supplied

Ultrastructure of parathyroid adenomas.

The ultrastructure of 12 cases of parathyroid adenomas is analyzed in the light of recent discoveries of biochemical functions of the parathyroids. Variants of parathyroid chief cells forming the adenomas are illustrated and cytologic details are explored. The correlation of cytoplasmic structures with hormone synthesis, transfer, secretion and intracellular lysosomal degradation is reviewed. A hormone secretory cycle in parathyroid adenomas is not observed. Current knowledge of parathyroid biochemistry does support modulation of hormone production and degradation by parathyroid chief cells rather than a cyclic secretory activity. Unusual structures and alterations of the normal organelles found in parathyroid adenomas are described and illustrated. Contrary to detailed knowledge of hormone synthesis, little is known about other metabolic and structural alterations in these adenomas. The reasons for massive accumulation of lipid, glycogen and mitochondria remain to be explored. As yet, neither ultrastructural investigation nor better understanding of biochemical processes of hormone production have led to recognition of etiologic factors inducing parathyroid adenomas.

Adenoma↗
PubMed1976

[Cutaneous leiomyosarcoma and osteomedullary plasmocytoma with the demonstration of IgA-kappa paraprotein in serum and skin tumor].

A dermal leiomyosarcoma associated with a still asymptomatic osteomedullary plasmocytoma with IgA paraproteinemia develop-d rapidly in a 78-year-old man. The same paraprotein type IgA kappa was identified, with distinct decrease in concentration, in serum, sarcoma-tissue, and in the tumour-surrounding skin area by m-ans of immunoelectrophoresis, radial immunodiffusion, and Ouchterlony test. The immunochemical identity of the paraprotein, the course of the disease as followed clinically and immunochemically, and several histological criteria are in favour of monoclonal origin of the paraprotein from malignant plasmocytoma cells. The accumulation of paraprotein in the sarcoma tissue is primarily explained by the marked blood congestion of the tumour. To our knowledge no report exists in the medical literature of an association of dermal leiomyosarcoma and early paraproteinemic plasmocytoma. This coincidence may be only of chance but we rather suggest an immunopathological relation of both tumors due to a partial immune insufficiency caused by the preceding plasmocytoma, resulting in a diminished immunological "surveillance" of the organism and favouring the development of a new malignant cell population (i.e. leiomyosarcoma).

Aged↗
PubMed2002

Overexpression of v-myb oncogene or c-myb proto-oncogene in insect cells: characterization of newly induced nucleolus-like structures accumulating Myb protein.

The oncoprotein v-Myb induces myeloid leukemia and its cellular counterpart c-Myb is involved in the regulation of hematopoiesis. Although intensively studied, their precise subcellular localization is not known. In order to expand our knowledge in this respect, we used an artificial system overexpressing these proteins. We investigated the subcellular localization of Myb proteins in cultured non-synchronized insect cells transfected with recombinant baculoviruses overexpressing either v-myb oncogene or c-myb proto-oncogene. The cell expressing Myb proteins underwent extensive nuclear changes and exhibited distinct nuclear structures resembling nucleoli. The bulk of v-Myb and c-Myb proteins accumulated in such nucleolus-like structures which, according to the nucleolar nomenclature, we classified to three types: compact of enlarged size (type I), large ring-shaped (type II) and with nucleolonemas (type III). We investigated these structures for the presence of important nucleolar macromolecules in order to establish whether they were compatible with the function in the production of ribosomes. Strikingly, our results indicated that the different forms of these structures did not represent genuine nucleoli. They rather reflected progressive changes, induced by the virus infection and high expression of v-myb genes, accompanied by the formation of these prominent nucleolus-like structures highly enriched in Myb protein. Gradual changes in number of individual nucleolus-like forms during infection, increasing amount of Myb protein and DNA localized in them together with decreasing amount of RNA and their different interaction with viral particles indicate that the nucleolus-like structure of type I is a precursor of the type II and finally of the type III.

Animals↗
PubMed2006

Neuronal ceroid lipofuscinosis in a Vietnamese pot-bellied pig (Sus scrofa).

The neuronal ceroid ipofuscinoses (NCL) are a group of heritable, neurodegenerative, storage diseases, typically with an autosomal recessive mode of inheritance. Cytoplasmic accumulation of storage material in cells of the nervous system and, variably in other tissues, characterizes NCL. NCL has been reported in many animal species, but to the authors' knowledge, this is the first report of the disease in a pig. Blindness and seizures are common clinical signs of disease, neither of which was a feature in this pig. The lesions were restricted to the central nervous system, which was diffusely affected, with the most severe lesions in the hippocampus, cerebral cortex, and cerebellum. The histologic lesions included neuronal loss and gliosis, which contributed to mild cerebrocortical and cerebellar atrophy and accumulation of autofluorescent storage material in neurons and glial cells. The storage material had morphologic, histologic, and ultrastructural properties typical of NCL.

Animals↗
PubMed1991

Bioactivation of xenobiotics by formation of toxic glutathione conjugates.

Evidence has been accumulating that several classes of compounds are converted by glutathione conjugate formation to toxic metabolites. The aim of this review is to summarize the current knowledge on the biosynthesis and toxicity of glutathione S-conjugates derived from halogenated alkanes, halogenated alkenes, and hydroquinones and quinones. Different types of toxic glutathione conjugates have been identified and will be discussed in detail: (i) conjugates which are transformed to electrophilic sulfur mustards, (ii) conjugates which are converted to toxic metabolites in an enzyme-catalyzed multistep mechanism, (iii) conjugates which serve as a transport form for toxic quinones and (iv) reversible glutathione conjugate formation and release of the toxic agent in cell types with lower glutathione concentrations. The kidney is the main, with some compounds the exclusive, target organ for compounds metabolized by pathways (i) to (iii). Selective toxicity to the kidney is easily explained due to the capability of the kidney to accumulate intermediates formed by processing of S-conjugates and to bioactivate these intermediates to toxic metabolites. The influences of other factors participating in the renal susceptibility are discussed.

Alkanes↗
PubMed2000

The role of pyruvate dehydrogenase and acetyl-coenzyme A synthetase in fatty acid synthesis in developing Arabidopsis seeds.

Acetyl-coenzyme A (acetyl-CoA) formed within the plastid is the precursor for the biosynthesis of fatty acids and, through them, a range of important biomolecules. The source of acetyl-CoA in the plastid is not known, but two enzymes are thought to be involved: acetyl-CoA synthetase and plastidic pyruvate dehydrogenase. To determine the importance of these two enzymes in synthesizing acetyl-CoA during lipid accumulation in developing Arabidopsis seeds, we isolated cDNA clones for acetyl-CoA synthetase and for the ptE1alpha- and ptE1beta-subunits of plastidic pyruvate dehydrogenase. To our knowledge, this is the first reported acetyl-CoA synthetase sequence from a plant source. The Arabidopsis acetyl-CoA synthetase preprotein has a calculated mass of 76,678 D, an apparent plastid targeting sequence, and the mature protein is a monomer of 70 to 72 kD. During silique development, the spatial and temporal patterns of the ptE1beta mRNA level are very similar to those of the mRNAs for the plastidic heteromeric acetyl-CoA carboxylase subunits. The pattern of ptE1beta mRNA accumulation strongly correlates with the formation of lipid within the developing embryo. In contrast, the level of mRNA for acetyl-CoA synthetase does not correlate in time and space with lipid accumulation. The highest level of accumulation of the mRNA for acetyl-CoA synthetase during silique development is within the funiculus. These mRNA data suggest a predominant role for plastidic pyruvate dehydrogenase in acetyl-CoA formation during lipid synthesis in seeds.

Acetate-CoA Ligase↗
PubMed2000

Classification and pharmacology of antiarrhythmic drugs.

Despite the emergence of several forms of nonpharmacologic therapy for cardiac arrhythmias, antiarrhythmic drugs continue to play an important role in the management of patients with this common clinical problem. The key to the proper use of antiarrhythmic drugs is a thorough knowledge of their mode of action and pharmacology. The pharmacology of antiarrhythmic drugs is particularly important because patients with cardiac arrhythmias frequently have multiorgan disease, which may influence the metabolism and elimination of antiarrhythmic drugs. The accumulation of toxic amounts of these agents can lead to dire effects including, but not limited to, ventricular proarrhythmia and malignant bradycardia. The goals of pharmacologic therapy of cardiac arrhythmia are to provide the maximum benefit in terms of arrhythmia suppression while maintaining patient safety. To accomplish these goals, a knowledge of the pharmacology of several antiarrhythmic drugs is mandatory.

Aged↗
PubMed2006

In vivo expansion of two distinct dendritic cells in mouse livers and its impact on liver immune regulation.

Liver transplant tolerance in pigs, rats, and mice has been disclosed for decades, but the underlying mechanisms are not completely understood. Accumulating data indicate that residing dendritic cells (DC) are important in determining direction of immune responses in the liver. However, our knowledge remains very limited due to the difficulties in obtaining sufficient liver DC. Most of the previous studies were dependent on DC propagated in vitro with growth factors and cytokines. In this study, we adopted an approach to transfect genes into the mouse liver by tail vein injection of plasmid DNA. Transfection with plasmid granulocyte-macrophage colony-stimulating factor markedly expanded liver CD11c(+) DC mainly located in portal regions, while liver B220(+) DC were dramatically generated after injection with plasmid interleukin (IL)-3/CD40L largely present in the lobules. Although both were phenotypically mature and strong T-cell stimulators, CD11c(+)DC induced potent T-cell response while B220(+)DC induced T-cell hyporesponsiveness. Administration of CD11c(+)DC accelerated cardiac allograft rejection, while B220(+)DC significantly prolonged graft survival. This hyporesponsiveness is not due to inhibition of DC/T-cell interaction, but rather through an active process of stimulating T-cell apoptosis. Compared to B220(+) DC that expressed messenger RNA of (TLR) 1, 2, 6, 7, and 9, CD11c(+)DC expressed all TLR 1 to 9. TLR 9 ligation stimulated very high IL-12 in CD11c(+) DC, but high IL-10 and no IL-12 in B220(+) DC. In conclusion, through these mechanisms, liver DC may be actively involved in immune regulation in the liver.

Animals↗
PubMedDate not supplied

Characterization and identification of local defects in glass.

The most relevant defects in glasses are categorized and investigated by appropriate microanalytical techniques. Since these defects very often present a real challenge because of complex chemical and mineralogical properties, a multimethod approach is necessary to supplement or confirm the findings from scanning techniques. The combination of electron probe microanalysis/energy-dispersive x-ray (EPMA/EDX) and laser ablation inductively coupled plasma mass spectroscopy (LA-ICP-MS) allows the determination of element trace concentrations in a knot, a glassy defect, thus finally enabling the identification of a special source of the defect from otherwise nondistinguishable refractories. The type of crystals can be determined exactly by the use of EPMA and x-ray dispersion (XRD), stones (a crystalline agglomerate) are analyzed by EPMA/EDX pointing to a possible source for this defect; results on metallic inclusions, "filled bubbles," and surface defects are reported and defect sources are discussed. Since close cooperation with the production departments and knowledge of production techniques and conditions are necessary for the diagnosis to take appropriate countermeasures, an approach is presented which systematically accumulates all information into a data base. The structure of such "expert systems" is described, which leads to correlation of appearance, analytical data, and source of the defects for even more accurate diagnosis and faster reaction.

Journal Article↗
PubMed1995

Genetics of lung cancer: implications for early detection and prevention.

Human lung cancer is a complex disease originating in different cell types. In general, tumorigenesis in the lung appears to involve a complex series of molecular, genetic, and histopathologic events, leading to the transformation of normal cells to malignant cells. It is generally believed that it is the accumulation of biologic changes, not necessarily the order in which they occur, that could best describe the transformation of cells. Our knowledge of genetic changes during tumorigenesis in the lung is limited and comes from studies involving animal models and frankly malignant lung tissues. Such studies can be questioned as to their applicability in primary prevention. A vast majority of genetic changes occurring during the preclinical stage are yet to be documented. Study of these preclinical changes would offer a better opportunity for early detection and prevention. Oncogenes and tumor suppressor genes have potential for use as biomarkers in identifying high-risk groups and in early detection. The interaction between nature and nurture is nowhere as evident as in cancers of the lung, which are influenced by environmental exposure, familial inheritance, and metabolic phenotypes. The gene-environment interaction provides several targets for prevention and early detection. Biomarkers, if validated for specificity, sensitivity, and predictive values, could act as markers of exposure, susceptibility, progression, and disease. Validation of these markers, however, would require well-characterized, prospectively collected samples, representing normal, premalignant, malignant, invasive, and metastatic conditions. The NCI has started an initiative for a tissue bank of prostate, bladder, colorectum, head and neck, and lung cancers. Clinical and epidemiological information are also collected for each sample. Study of genetic and molecular changes in collected samples should shed light on the involvement of these changes in the transformation of normal to malignant tissues.

Biomarkers, Tumor↗
PubMed2005

Beta-methyl-xyloside: positive effect on xylanase induction in Cellulomonas flavigena.

Synthesis of extracellular xylanase in Cellulomonas flavigena is induced in the presence of xylan and sugarcane bagasse as substrates. The essential factors for efficient production of xylanase are the appropriate medium composition and an inducing substrate. The increase in xylanase production levels in C. flavigena were tested with a number of carbon sources and different culture conditions. Xylose, arabinose, glycerol and glucose did not induce xylanase production in this microorganism. beta-Methyl-xyloside (beta-mx), a structural analog of xylobiose, also did not induce xylanase when used as the sole carbon source, but when xylan or sugar cane bagasse was supplemented with beta-mx, extracellular xylanase production increased by 25 or 46%, respectively. The response of C. flavigena to xylan plus beta-mx was accompanied by a significant accumulation of reducing sugar, an effect not observed with the combination sugarcane bagasse plus beta-mx as substrate. To our knowledge, this is the first report on the effect of beta-mx on the induction of xylanase in C. flavigena.

Cellulomonas↗
PubMed2004

Can we disentangle life course processes of accumulation, critical period and social mobility? An analysis of disadvantaged socio-economic positions and myocardial infarction in the Stockholm Heart Epidemiology Program.

The accumulation hypothesis would propose that the longer the duration of exposure to disadvantaged socio-economic position, the greater the risk of myocardial infarction. However there may be a danger of confounding between accumulation and possibly more complex combinations of critical periods of exposure and social mobility. The objective of this paper is to investigate the possibility of distinguishing between these alternatives. We used a population based case-control study (Stockholm Heart Epidemiology Programme) of all incident first events of myocardial infarction among men and women, living in the Stockholm region 1992-94. The analyses were restricted to men 53-70 years, 511 cases and 716 controls. From a full occupational history each subject was categorized as manual worker or non-manual at three stages of the life course, childhood (from parent's occupation), at the ages 25-29 and 51-55, resulting in 8 possible socio-economic trajectories. We found a graded response to the accumulation of disadvantaged socio-economic positions over the life course. However, we also found evidence for effects of critical periods and of social mobility. A conceptual analysis showed that there are, for theoretical reasons, only a limited number of trajectories available, too small to form distinct empirical categories of each hypothesis. The empirical task of disentangling the life course hypotheses of critical period, social mobility and accumulation is therefore comparable to the problem of separating age, period, and cohort effects. Accordingly, the interpretation must depend on prior knowledge of more specific causal mechanisms.

Aged↗
PubMed1992

Cytokines, platelet activating factor and eosinophils in asthma.

Understanding of the pathogenesis of asthma has increased considerably during the past few years. These advances were possible through scientific progress in three areas which contribute to this complex and multifaceted disease: (a) the much clearer understanding of eosinophil function; (b) the defining of lipid mediators in tissue inflammation and bronchial obstruction; and (c) the growing knowledge about the biological action of a new class of protein hormones, collectively called cytokines. In line with this, evidence has accumulated of how these components may interact with each other in providing the basis of inflammatory processes in asthma. Hence it seems appropriate to review the potential implications of this new information for the pathogenesis and therapy of this disease.

Animals↗
PubMed1995

Regulation of pre-mRNA processing by src.

BACKGROUND: Changes in gene expression in response to external signals provide a key mechanisms for the regulation of higher eukaryotic cell functions. The importance of transcriptional control in the response of cells to growth factors and cytokines has been extensively documented, but gene expression has also been shown to be controlled at other levels, such as the stability of mRNA in the cytoplasm, its localization and translation. By contrast to transcriptional control, little is known of the contribution of pre-mRNA nuclear processing to the regulation of gene expression, as most of our knowledge of pre-mRNA processing in vivo is indirect, being inferred from comparisons of transcription rates and levels of mRNA accumulation. RESULTS: In this study, we have used as a model the well-characterized maturation pathway of transcripts of the cytokine, tumour necrosis factor beta (TNF beta). We have used the murine TNF beta gene as a reporter for pre-mRNA processing, using a co-transfection approach to investigate whether overproduction of proteins involved in signal transduction influences the processing of TNF beta transcripts. Although transfection of both activated ras and src genes led to an increase in RNA accumulation in the nuclear and cytoplasmic compartments, as expected from their transactivation of the TNF beta expression vector, only src induced a modification of RNA processing. Comparison of several modes of src activation indicated that two distinct effects of src on pre-mRNA processing can be coupled: one involves slowing down splicing and the other allows the export of partially spliced transcripts. These effects can be observed not only on the three introns of TNF beta but also on transcripts from a beta globin expression vector. DISCUSSION: We have characterized how the processing of transcripts of TNF beta and beta globin is regulated by the signal transduction pathway that includes the Src protein, establishing that external signals have the capacity to regulate gene expression at a post-transcriptional level within the nucleus. Src seems to act on a general mechanism of splicing and/or mRNA transport, but its biologically relevant targets are likely to be restricted to genes for which either alternative processing pathways are in competition, or the kinetics of splicing is critical. This regulation could reflect a modulation by Src of the activity of components of the splicing and transport machineries, but could also involve RNA-binding proteins, which have been shown to interact with Src.

3T3 Cells↗
PubMed1999

Lymph node staging in clinically localized prostate cancer.

Pelvic lymph node involvement is an adverse prognostic factor in clinically localized prostate cancer, and a knowledge of nodal status is important for patient management. Whereas nodal disease has been widely regarded as incurable, evidence is now accumulating that some men with lymph node involvement may benefit from radical multimodality treatment approaches. Pelvic nodal status may be assessed by predictive nomograms, by imaging studies and by surgery. The pros and cons of each method are discussed together with the prospects for future development. Optimal strategies combining the different diagnostic approaches for the detection of lymph node metastases are considered in the context of the changing therapeutic implications of nodal disease.

Journal Article↗
PubMed1994

Expression of a maize proteinase inhibitor gene is induced in response to wounding and fungal infection: systemic wound-response of a monocot gene.

The isolation and characterization of cDNA and genomic clones encoding a proteinase inhibitor protein (MPI) in maize is reported. Accumulation of the MPI mRNA is induced in response to fungal infection in germinating maize embryos. The expression pattern of the MPI gene, in healthy and fungal infected maize tissues, was examined and compared with the expression pattern of a gene that codes for a pathogenesis-related protein (the PRms protein) from maize. These two genes are induced by fungal infection, however different signals trigger their activation. Accumulation of the proteinase inhibitor mRNA is more a consequence of the wound produced by the penetration and colonization of the host tissues by the pathogen, than the result of a direct molecular recognition of the pathogen by the plant, as is the case for the induction of the PRms gene. Wounding, or treatment with abscisic acid or methyl jasmonate, stimulate MPI mRNA accumulation, but not PRms mRNA accumulation. Local and systemic induction of the MPI gene expression in response to wounding occurs in maize plants. To the authors' knowledge, this is the first example of a gene from a monocotyledonous species that clearly shows a systemic wound response. The possible functional implications for the existence of different signal transduction pathways that simultaneously activate a battery of defense mechanisms against potential pathogens are discussed.

Abscisic Acid↗