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PubMedDate not supplied

Marriage of a medium-term liver model to surrogate markers--a practical approach for risk and benefit assessment.

The need for a reliable medium-term alternative to traditional long-term rodent test protocols for carcinogen risk assessment is pressing given the immense variety of compounds being developed for introduction into the human environment. The established lack of a complete correlation between mutagenicity and carcinogenicity means that recourse must be made to an in vivo model. Optimally, this model should be able to detect not only complete carcinogenic or promoting potential but also any ability to inhibit neoplasia. In order to be effective, it must take into account the available detailed knowledge on mechanisms of action of carcinogens and modulating agents. The Ito model, for which a uniquely comprehensive set of background data has already been accumulated, has a solid scientific basis; this model utilizes quantitative data for glutathione S transferase-positive foci as the preneoplasia-based surrogate end point (PSE). A very practical candidate for routine application, its predictive power, its flexibility, and its capacity to incorporate a range of mechanism-based surrogate end points (MSEs) provide a powerful tool for attainment of the twin goals of detecting carcinogenic agents and identifying promising chemopreventors.

Animals↗

PubMed1987

Developing price, charge, and cost rationales.

The health care industry has experienced some turbulent years recently, and the end does not seem near. Payment methods are being established that are entirely new and have not stood the test of time. For hospitals to remain competitive, they must be able to understand and master the different payment methods. The one common thread discussed throughout this article is that intelligent decisions concerning payment cannot be made until the costs are known. Hospitals cannot commit to these contracts and cannot expect to perform well and generate profits without this knowledge--without detailed cost information, it is a "stab in the dark." A good working relationship between cost accounting and materiel management is needed to accumulate timely and accurate information. This is why their relationship is so important. Those hospitals that master this information requirement will have the best chance of survival in the increasingly competitive field of health care.

Economic Competition↗

PubMed2004

[Inflammation in acute coronary syndromes: mechanisms and clinical implications].

Inflammation plays a pivotal role in the pathogenesis of atherosclerosis and its complications. In particular, atherosclerosis is an active process and the inflammatory component appears to be particularly correlated with the development of acute coronary syndromes (ACS). Accumulating data demonstrate that in ACS, elevated levels of circulating inflammatory markers, such as C-reactive protein, predict an unfavorable cardiovascular outcome. A better knowledge of the molecular and cellular mechanisms of inflammation might not only further improve prognostic stratification but also allow us to identify novel therapeutic targets. The present review summarizes the mechanisms of the inflammatory response in ACS, its clinical implications, and the potential treatment strategies to contrast this phenomenon.

Acute Disease↗

PubMed2005

[Current problems of hygiene and epidemiology].

In this review, the data available in the literature concerning determinants of human health from the public health point of view have been summarized. Presented newest concepts of human health include genomic and proteomic perspectives in the complex web of interactions between genes and environment. In 2002 epidemiologist and hygienist also has an access to an almost complete description of a single human genome but the challenges remain to move from the description to understanding the function of the genome. Studying the role of molecular determinants of human health is an area of research that has gained attention, particularly during the past 50 years, since the structure of DNA helix has solved. This field will become more dynamic one in the near future and the important data will rapidly accumulate. Further researches are clearly needed to determine not only carcinogenic potential of human ecosystems, but also to establish new methods of risk assessment. The knowledge gained will be crucial in prophylactic health care systems.

Environmental Illness↗

PubMed2006

Morquio's syndrome: severe aortic regurgitation and late pulmonary autograft failure.

A 44-year-old woman underwent a Ross procedure for severe aortic regurgitation at the age of 32 years. She had been diagnosed in childhood with spondyloepiphyseal dysplasia and a bicuspid aortic valve. At surgery, a tricuspid aortic valve with chondroid metaplasia and fibrosis was reported. Biochemical and genetic evaluation in this patient confirmed the diagnosis of mucopolysaccharidosis IV type B (MPS IV), otherwise known as Morquio's syndrome. This autosomal-recessive inherited syndrome is characterized by the accumulation of keratin sulfate in connective tissue and various other organs. Cardiac (notably valvular) involvement has been well described in the literature. To the authors' knowledge, this is the first reported case of valve replacement or Ross procedure for this condition. This woman presented 12 years after her initial valve surgery with progressive dyspnea. Echocardiographic examination revealed severe pulmonic autograft regurgitation without a dilated aortic root, together with severe stenosis of the pulmonary homograft. It is postulated that the underlying metabolic abnormality may have led to progressive pulmonary autograft failure and to accelerated dysfunction and stenosis of the pulmonary homograft. It is likely that a mechanical prosthesis would have been a better therapeutic option if the preoperative diagnosis of MPS IV had been made.

Adult↗

PubMedDate not supplied

[Physiopathology of iron metabolism and hemochromatosis: interrelationships, assessment and pathogenesis of iron overload, screening].

Fundamental aspects of iron metabolism relate to the dynamic processes of metal plasma transport as well as cell storage and efflux. Transferrin not only carries iron in the plasma but also delivers it to the various cells by binding to a diffuse specific cell receptor; it also acts by chelating cell iron. Ferritin co-operates by storing iron in the cell. By a still unknown regulatory mechanism, iron, from the ferritin pool, is redistributed in the cell to a cytosolic, easily chelatable, "transit" pool or to a degradative lysosomal hemosiderin pool from which it is slowly released outside the cell. Iron overload, such as that typical of hyperhemolysis or hemochromatosis, profoundly impairs its metabolism by saturating and/or altering transferrin and ferritin, by freeing iron from any regulated transport, thus allowing parenchymal deposition and damage. An important aspect still awaiting clarification relates to the different storage of excess iron in the parenchymal cells, as in hemochromatosis, or in the reticuloendothelial system such as in hemosiderosis. Studies using cellular models attempt to evaluate such differences in terms of altered properties of the iron proteins or their cell receptors, and of the different cell responsivity to non-transferrin iron. In the expectation of better knowledge, attention should be concentrated, from a clinical standpoint, on precise assessment of iron deposits in the tissues with the aim of preventing its excessive accumulation and parenchymal damage. In hemochromatosis, the risk of iron overload is evaluated by HLA typing.

HLA Antigens↗

PubMed1986

Limitations of radiolabeled monoclonal antibodies for localization of human neoplasms.

Tumor-associated monoclonal antibodies were radiolabeled with 125I and 131I and given i.v. in pairs to 19 patients 1-26 days prior to surgical excision of primary and metastatic breast, ovarian, and gastrointestinal tumors. For individual patients each monoclonal antibody was designated as specific or nonspecific according to prior immunoperoxidase staining results on the appropriate target neoplastic tissues. Quantitation of antibody uptake was performed on resected normal and neoplastic tissues. Although good tumor:non-tumor ratios were obtained with the specific antibodies (maximal tumor:blood ratio, 35.8:1 at 12 days postadministration), the absolute amount of radiolabel detected in tumors was small (mean value of 0.015% of total injected amount per g of tumor occurring 1 day postadministration). Furthermore, both specific and nonspecific antibodies accumulated in normal lymph nodes to a significant extent (mean value of 0.0026% of total injected amount per g of tissue occurring 1 day postadministration). Knowledge of such data is essential prior to considering therapeutic uses of radiolabeled monoclonal antibodies.

Adult↗

PubMed1981

The ontogeny of the ruminant immune system and its significance in the understanding of maternal-fetal-neonatal relationships.

Considerable information is now beginning to accumulate on the ontogeny of immune responses in the ovine fetus. The fetal lamb has served as an important model for much of our present knowledge. Many critical questions remain to be answered in the ruminants. Much of this information provides a basis for a better understanding of the susceptibility of the fetus, the character of lesions and the events leading to persistent infections in congenital infections. The role that hormones associated with pregnancy plays in active and passive immunity in maternal, fetal and neonatal systems needs further definition. An understanding of these may make it possible to assist in reducing infections leading to congenital or neonatal disease.

Animals↗

PubMed1984

The effect of hormones on proton compartmentation in hepatocytes.

Liver mitochondria isolated from rats treated acutely with glucagon exhibit higher respiration-dependent H+ ion gradients across the mitochondrial inner membrane than mitochondria from control rats. It has been suggested that similar increases in mitochondrial delta pH in situ could stimulate gluconeogenesis, chiefly because the transport of pyruvate into mitochondria would increase in response to the increase in mitochondrial matrix pH. In order to determine whether the increased delta pH observed in vitro in isolated mitochondria also occurs in situ, the effect of glucagon on the pH in the cytosol and mitochondria matrix spaces of isolated hepatocytes was determined. For qualitative results, the spectral responses of intracellularly trapped 6-carboxyfluorescein was used to monitor cytosol pH, while fluorescein-loaded hepatocytes were used to monitor the mitochondrial pH. Hepatocytes were incubated with the diacetate ester derivatives of these dyes. The esters are permeable to the cell membranes, but are rapidly hydrolyzed in the cells. The free unesterified dyes are relatively impermeable to the cell membranes. After being trapped in the cell, 6-carboxyfluorescein remains localized in the cell cytosol, whereas fluorescein is taken up by the mitochondria as a function of the mitochondrial delta pH. In order to quantitate the actual pH in these compartments, the spectral responses (490-465 nm) of 6-carboxyfluorescein-loaded hepatocytes were used to determine the cytosolic pH. Calibration of these responses was obtained within the cell by determination of the dye's differential absorption coefficient (epsilon 490-465 nm) in various high K+ buffers after equilibration of the internal and external pH with valinomycin and the uncoupler 1799. All absorbance values were corrected for dye leakage. Equal hematocrits of unloaded cells were used to correct for absorbance contributions from cellular constituents. The mitochondrial pH was determined by a combination of the indicator dye and [14C]5,5'-demethyloxazolidine-2, 4-dione (DMO) distribution ratio methods. The weak acid DMO freely distributes across the plasma membrane and mitochondrial membrane in whole cells according to the pH gradient across each membrane. Knowledge of the cytoplasmic pH from the 6-carboxyfluorescein data allows the expected distribution of DMO across the plasma membrane to be calculated. The excess accumulation of DMO in intact hepatocytes over that predicted from the plasma membrane pH gradient alone was then used to calculate the pH gradient across the mitochondrial inner membrane. The effects of valinomycin, uncouplers, and hormones on the pH in cytosolic and mitochondrial compartm

Animals↗

PubMed1993

Subepithelial mucinous corneal dystrophy. Clinical and pathological correlations.

We describe a family with an unusual autosomal dominant anterior corneal dystrophy. The onset was characterized by frequent, recurrent corneal erosions in the first decade. This subsided during adolescence and was followed by progressive decreased vision. Slit-lamp examination revealed bilateral subepithelial opacities and haze, involving the entire cornea, but most dense centrally. Histopathological study revealed a subepithelial band of eosinophilic, periodic acid-Schiff-positive, alcian blue-positive, hyaluronidase-sensitive material anterior to Bowman's layer. Electron microscopy demonstrated subepithelial deposition of fine fibrillar material consistent with glycosaminoglycan. Immunohistochemical analysis indicated that the accumulated material contained a combination of chondroitin 4-sulfate and dermatan sulfate. This unique condition clinically resembled Grayson-Wilbrandt dystrophy, but differed histochemically. To our knowledge, this anterior corneal dystrophy has not previously been reported, and it is best described by the name "subepithelial mucinous corneal dystrophy."

Aged↗

PubMed1999

Adaptive design improvements in the continual reassessment method for phase I studies.

The continual reassessment method (CRM) enables full and efficient use of all data and prior information available in a phase I study. However, despite a number of recent enhancements to the method, its acceptance in actual clinical practice has been hampered by several practical difficulties. In this paper, we consider several further refinements in the context of phase I oncology trials. In particular, we allow the trial to stop when the width of the posterior 95 per cent probability interval for the maximum tolerated dose (MTD) becomes sufficiently narrow (that is, when the information accumulating from the trial data reaches a prespecified level). We employ a simulation study to evaluate five such stopping rules under three alternative states of prior knowledge regarding the MTD (accurate, too low and too high). Our results suggest our adaptive designs preserve the CRM's estimation ability while offering the possibility of earlier stopping of the trial.

Antineoplastic Agents↗

PubMed2001

Central nervous system perivascular cells are immunoregulatory cells that connect the CNS with the peripheral immune system.

Perivascular cells are a heterogeneous population found in the central nervous system (CNS) and the peripheral nervous system (PNS). Several terms are used for these cells, including perivascular cells, perivascular macrophages, perivascular microglia, fluorescent granular perithelial cells (FGP), or Mato cells. Different terminology used may reflect subpopulations of perivascular cells within different anatomic regions and experimental paradigms, neuropathological conditions, and species studied. Different terminology also points to the lack of clear consensus of what cells are perivascular cells in different disease states and models, especially with breakdown of the blood-brain barrier (BBB). Despite this, there is consensus that perivascular cells, although a minor component of the CNS, are important immunoregulatory cells. Perivascular cells are bone marrow derived, continuously turn over in the CNS, and are found adjacent to CNS vessels. Thus, they are potential sensors of CNS and peripheral immune system perturbations; are activated in models of CNS inflammation, autoimmune disease, neuronal injury and death; and are implicated as phagocytic and pinocytotic cells in models of stroke and hypertension. Recent evidence from our laboratory implicate perivascular cells as primary targets of human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) infection in the CNS of humans and macaques. This article reviews current knowledge of perivascular cells, including anatomic location and nomenclature and putative immunoregulatory roles, and discusses new data on the infection of these cells by SIV, their accumulation after SIV infection, and a possible role of the immune system in SIV encephalitis.

AIDS Dementia Complex↗

PubMed2005

Characterization of serine/cysteine protease inhibitor alpha1-antitripsin from meconium-instilled rabbit lungs.

We have recently purified from meconium-instilled rabbit lungs a novel serine proteinase inhibitor, with an apparent molecular mass of 50 kDa, which we assign to be alpha1-antitripsin. We hypothesize that serpin may attenuate pulmonary inflammation and improve surfactant function after meconium aspiration. Alpha1-antitripsin is a member of the proteinase inhibitor (serpin) superfamily and inhibitor of neutrophil elastase, and it can be identified as a member of the family by its amino acid sequence due to the high degree of conserved residues. Alpha1-antitripsin is synthesized by epithelial cells, macrophages, monocytes, and neutrophils. Deficiency in alpha1-antitripsin leads to exposure of lungs to uncontrolled proteolytic attack from neutrophil elastase or other damaging factors culminating in lung destruction and cell apoptosis. We hypothesize that accumulation of alpha1-antitripsin in the lungs serves as a predisposed protection against meconium-induced lung injury. In this paper, we show how this knowledge can lead to the development of novel therapeutic approaches for treatment of MAS.

Animals↗

PubMed1980

Accumulation of Tx-99m phosphonate complexes in metastatic lesions from colon and lung carcinomas.

Cases are presented in which Tc-99m methylene diphosphonate accumulated in a lung metastasis from well differentiated adenocarcinoma of the colon, and in a hepatic metastasis from oat cell carcinoma of the lung. To our knowledge, this is the first report of Tc-99m phosphonate complexes concentrated in a pulmonary metastasis of colonic caecinoma or in a hepatic metastasis of oat cell lung carcinoma. The exact mechanism for this non-osseous uptake of bone scanning agents is still unknown.

Adenocarcinoma↗

PubMed1994

Cyclic ADP-ribose: a calcium mobilizing metabolite of NAD+.

Mobilization of Ca+2 from intracellular stores is a signalling mechanism that is of fundamental importance to many cellular processes. It is mediated by two major mechanisms, the inositol 1,4,5-trisphosphate pathway and the Ca+2-induced Ca+2 release process. A naturally occurring metabolite of NAD+ called cyclic ADP-ribose has been discovered recently and shown to be as effective as inositol 1,4,5-trisphosphate in mobilizing Ca+2 stores in sea urchin eggs, a marine invertebrate cell, as well as several mammalian cells. This article reviews the accumulating evidence that indicates cyclic ADP-ribose may function as a physiological regulator of the Ca+2-induced Ca+2 release process and the current knowledge about its receptor as well as the enzymes involved in its metabolism.

ADP-ribosyl Cyclase↗

PubMed1989

Mitochondrial genome in animal cells. Structure, organization, and evolution.

In the past decade, the development of new DNA, RNA, and protein technologies has greatly incremented the knowledge about the organization and expression of mitochondrial DNA. The complete base sequence of mitochondrial DNA of several animals is known and many data are rapidly accumulating on the mitochondrial genomes of other systems. Here we discuss the results so far obtained that disclosed unexpected features of mitochondrial genetics. Furthermore, mitochondrial DNA has become established as a powerful tool for evolutionary studies in animals. Evidences are presented demonstrating that the evolution of mitochondrial DNA has proceeded in different ways in the various taxonomic groups. Data on heteroplasmic animals, which demonstrate the rapid evolution of mitochondrial DNA, are also presented.

Animals↗

PubMed1992

Expression of protease nexin-II in human dorsal root ganglia. A correlative immunocytochemical and in situ hybridization study.

Protease nexin-II (PN-II) is a potent chymotrypsin inhibitor that forms SDS-stable inhibitory complexes with epidermal growth factor binding protein, the gamma-subunit of nerve growth factor, and trypsin, and represents the secreted form of the amyloid beta-protein precursor (APP) that contains the Kunitz-type protease inhibitor domain. To determine the expression of PN-II within the peripheral nervous system, human dorsal root ganglia were processed for immunocytochemistry using well-characterized monoclonal antibodies against PN-II and for in situ hybridization studies using 35S-RNA PN-II probes for both APP751 and APP770. Highly specific immunoperoxidase staining of PN-II was demonstrated within the cytoplasm of dorsal root ganglia neurons and their processes in cryostat (fresh frozen) and vibratome (paraformaldehyde-fixed) sections. In situ hybridization using an anti-sense 35S-RNA PN-II probe demonstrated the presence of intense neuronal labeling. Labeling was not observed when the corresponding sense 35S-RNA PN-II probe was used. Although the precise functional role of PN-II/APP is not clear, the accumulation of amyloid beta-protein within the neuropil appears to be one of the earliest events in the pathogenesis of Alzheimer's disease (AD). Thus knowledge of the cell populations expressing the PN-II/APP gene would certainly be helpful for studies of the molecular mechanisms leading to the morphological and functional changes of AD. The results of this study clearly establish the expression of PN-II and its mRNA within the dorsal root ganglia neurons and their processes, and provide another point of departure for studies of the molecular mechanisms underlying the deposition of amyloid beta-protein and its relationships to the formation of neuritic plaques and neurofibrillary tangles.

Amyloid beta-Protein Precursor↗

PubMed2006

Somatic stem cells and the origin of cancer.

Most human cancers derive from a single cell targeted by genetic and epigenetic alterations that initiate malignant transformation. Progressively, these early cancer cells give rise to different generations of daughter cells that accumulate additional mutations, acting in concert to drive the full neoplastic phenotype. As we have currently deciphered many of the gene pathways disrupted in cancer, our knowledge about the nature of the normal cells susceptible to transformation upon mutation has remained more elusive. Adult stem cells are those that show long-term replicative potential, together with the capacities of self-renewal and multi-lineage differentiation. These stem cell properties are tightly regulated in normal development, yet their alteration may be a critical issue for tumorigenesis. This concept has arisen from the striking degree of similarity noted between somatic stem cells and cancer cells, including the fundamental abilities to self-renew and differentiate. Given these shared attributes, it has been proposed that cancers are caused by transforming mutations occurring in tissue-specific stem cells. This hypothesis has been functionally supported by the observation that among all cancer cells within a particular tumor, only a minute cell fraction has the exclusive potential to regenerate the entire tumor cell population; these cells with stem-like properties have been termed cancer stem cells. Cancer stem cells can originate from mutation in normal somatic stem cells that deregulate their physiological programs. Alternatively, mutations may target more committed progenitor cells or even mature cells, which become reprogrammed to acquire stem-like functions. In any case, mutated genes should promote expansion of stem/progenitor cells, thus increasing their predisposition to cancer development by expanding self-renewal and pluripotency over their normal tendency towards relative quiescency and proper differentiation.

Animals↗