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PubMed1988

Update: Epstein-Barr virus-related disease.

The widespread application of molecular virologic technology has resulted in a rapid expansion in our knowledge of the physical, biologic, and clinical properties of EBV. As data continue to accumulate, we may better understand the pathogenesis of, and more clearly define diseases associated with, primary and reactivated infection due to this virus. The development of new antiviral agents and recombinant or subunit vaccines will permit more effective treatment, and possibly prevention, of disease and long-term sequelae associated with EBV infection.

Acute Disease↗
PubMed1980

Spondyloepiphyseal dysplasia congenita. A comparative study of chondrocytic inclusions.

Spondyloepiphyseal dysplasia congenita is a short-trunk chondrodysplasia trait. The abnormalities are present at birth and involve primarily the spine, the epiphyses of long bones, and the pelvis. Postmortem examinations of two patients with this disease who died shortly after birth showed a mild disorganization of chondrocytic columnization in the physeal growth zone. The chondrocytes contained PAS-positive cytoplasmic inclusions after diastase digestion to eliminate glycogen. Ultrastructural examination of the inclusions in one patient showed them to be accumulations of finely granular material in dilated cisterns of rough endoplasmic reticulum. To our knowledge, similar findings have been seen only in three other types of chondrodysplasia. The inclusions, which therefore are of diagnostic importance, may be of importance also in reflecting the primary metabolic abnormality.

Cartilage↗
PubMed1980

[Present views of lymphocyte growth and differentiation].

In recent years, a large body of information has been accumulated on the origin and differentiation of lymphocytes. According to the present state of knowledge, their ontogeny can be outlined as follows: the pluripotent stem cell originates the lymphatic progenitors, which undergo a series of differentiation events within the microenvironment of the primary lymphatic organs (bone marrow and thymus). Thus lymphatic precursors appear, which finally give rise to mature T- and B-lymphocytes. These events are accompanied by distinct changes in cell markers, mostly surface markers, which have been clearly documented. Some controversy does exist as to whether T and B lineages stem from a common lymphatic progenitor, since recent evidence suggests that B lymphocytes, but not the T, might share a common progenitor with myeloid lineages (hemocytoblast). T-cell maturation starts in the thymic cortex, and under the influence of the soluble thymic factor(s) it progresses in the several post-thymic locations, until final maturation. This process goes from immature (To) to semi-mature (T1) and mature (T2) lymphocytes, these latter mostly characterized by the absence of TdT and by the property to form E-rosettes with SRBC and respond to mitogens. Circulating mature T-lymphocytes display a considerable degree of heterogeneity in terms of functional properties; in this way, various T-subpopulations have been identified on the ground of recognized different properties. The sequence of maturational events of B-lineage takes place within the bursa-equivalent sites. This includes an antigen-independent stage with early B precursors (B0 - B1 - B2), and an antigen-driven maturational phase which actually produces the plasma cells. Among the early B-precursors (B-virgin population), memory cells arise following the antigenic stimulation. Also at that stage, B-cells are highly susceptible to tolerance induction. B-circulating lymphocytes are mainly characterized by S-Ig, Fc receptors, and complement receptors.

B-Lymphocytes↗
PubMed1994

Abnormal accumulation of prion protein mRNA in muscle fibers of patients with sporadic inclusion-body myositis and hereditary inclusion-body myopathy.

Sporadic inclusion-body myositis is the most common progressive muscle disease of older patients. The muscle biopsy demonstrates mononuclear cell inflammation and vacuolated muscle fibers containing paired helical filaments and 6 to 10-nm fibrils, both resembling those of Alzheimer brain, and Congo-red positivity. Hereditary inclusion-body myopathy designates patients cytopathologically similar but without inflammation. In both muscle diseases, prion, and several proteins characteristic of Alzheimer brain--eg, beta-amyloid protein and hyperphosphorylated tau (which normally are expressed mainly in neurons), and apolipoprotein E--are abnormally accumulated in vacuolated muscle fibers, by unknown mechanisms. We now demonstrate in both muscle diseases that prion mRNA is strongly expressed in the vacuolated muscle fibers, which suggests that their accumulated prion protein results, at least partly, from increased gene expression. This, to our knowledge, is the first demonstration of abnormally increased prion mRNA in human disease. Another novel finding is the increased prion mRNA in human muscle macrophages, and both increased prion protein and prion mRNA in regenerating muscle fibers. The latter indicates that prion may play a role in human muscle development.

Adult↗
PubMed1996

Defining and analyzing cohorts using molecular markers of cancer risk.

Cancer is currently regarded to be the phenotypic expression of an accumulation of heritable alterations in the regulators of cell growth and differentiation. Though detailed knowledge of the sequence and in vivo mechanistic effects of these alterations is rudimentary for most, if not all, cancers, their identification does offer the potential for classifying groups of individuals who are heterogeneous with respect to their cancer risks, into more nearly homogeneous subgroups. In this paper, we illustrate the value of using markers, which we define as any manifestation of cellular molecular diversity, to increase subgroup homogeneity. In the context of time-to-event data, we demonstrate for both somatic mutations (acquired p53 abnormalities in gastric mucosal cells) and inherited polymorphisms (polymorphisms in the phase 1 and 2 detoxifying enzymes) how knowledge regarding the population frequency of the marker the effect of the marker on the risk of cancer development, and/or the effect of the marker on response to therapy, can be used to plan and analyze such trials. Using as paradigms demographic features of the recently begun Shandong precancerous gastric lesion intervention trial, and the recently completed alpha-tocopherol beta-carotene (ATBC) lung cancer prevention study, we review the information, assumptions, and mathematical structure required for planning cancer prevention trials. We graphically demonstrate how informative markers make available strategies for selection, stratification, and optimal weighing, which, when properly implemented, increase the power of tests of effective cancer prevention agents.

Adult↗
PubMed2006

Use of research results in policy decision-making, formulation, and implementation: a review of the literature.

This paper offers a critical review of the theoretical literature on the relationship between the production of scientific knowledge and its use in policy formulation and implementation. Extensive academic output, using a diversity of approaches and analytical frameworks, has sought to systematize knowledge transfer categories and strategies with a view to improving the application of scientific knowledge. A considerable part of this thinking addresses the problem from a more traditional perspective, which (explicitly or implicitly) regards research results as an "accumulable product", depicts the decision-making process simplistically and linearly, and thus restricts strategies to the suiting of research endeavors to needs. Newer approaches place greater importance on the complexity of policymaking and the knowledge production process, which are integrated into and explained in particular political and institutional settings. Although the application of knowledge transfer ideas to health policy and systems research does generate some interesting contributions, a long process of theoretical thinking lies ahead.

Biomedical Research↗
PubMed2004

Cardiovascular nursing in RN and higher education in Swedish universities: a national survey.

Cardiovascular nursing (CVN) is rapidly developing and has accumulated a large amount of evidence to support interventions aimed at reducing suffering and hastening recovery. However, knowledge of the extent and content of CVN training in Sweden is lacking. The aim of this study was therefore to identify and describe CVN in the Swedish RN education as well as in higher education, with reference to type of course and credits, content, area and target group. A nationwide survey was carried out in Sweden at all university level nursing schools (N=26) by means of a 25-item questionnaire, which was analysed by descriptive statistics. The findings show that 69% and 23% of the schools awarded 0-1 credits [0-1.5 European Credit Transfer and Accumulation System (ECTS)] and 2-3 credits (3-4.5 ECTS), respectively for cardiology/CVN in the RN education. Target areas outside the hospital setting reported by 23% and 19% of nursing schools were primary health care and community care, respectively. Special target groups in addition to the general public were the elderly (42%) and women (58%). Advanced courses in CVN comprising 10-40 credits (15-60 ECTS) were held by 27% of nursing schools, but no school had a specialist or Master level education. Important educational implications from the study of the RN education are the establishment of a minimum credit figure and to reach out into primary health care.

Cardiology↗
PubMed2006

Ultrafine particle-lung interactions: does size matter?

Epidemiological studies continue to indicate associations between exposure to increased concentrations of ambient fine and ultrafine particles and adverse health effects in susceptible individuals. The ultrafine particle fraction in the ambient atmosphere seems to play a specific role. Yet, the dosimetry (including deposition patterns in the respiratory tract and, particularly, the biokinetic fate of ultrafine particles) is not fully understood. In contrast to fine particles, inhaled ultrafine particles seem to follow different routes in the organism. Cardiovascular effects observed in epidemiological studies triggered the discussion on enhanced translocation of ultrafine particles from the respiratory epithelium towards circulation and subsequent target organs, such as heart, liver, and brain, eventually causing adverse effects on cardiac function and blood coagulation, as well as on functions of the central nervous system. Current knowledge on systemic translocation of ultrafine particles in humans and animal models is reviewed. Additionally, an estimate of accumulating particle numbers in secondary target organs during chronic exposure is extrapolated from long-term translocation data obtained from rats. Toxicological studies aim to provide the biological plausibility of health effects of ultrafine particles and to identify cascades of mechanisms that are causal for the gradual transition from the physiological status towards pathophysiologcal alterations and eventually chronic disease. Considering the interaction between insoluble ultrafine particles and biological systems (such as body fluids, proteins, and cells), there still are gaps in the current knowledge on how ultrafine particles may cause adverse reactions. This paper reviews the current concept of interactions between insoluble ultrafine particles and biological systems.

Aerosols↗
PubMed2026

On the state of protein function prediction: a report on the fourth CAFA challenge.

BACKGROUND: The Critical Assessment of Functional Annotation (CAFA) is a community effort held to understand the field of computational protein function prediction. Every three years, since 2010, the organizers initiate an experiment to collect function predictions on a large set of proteins and then evaluate the performance of predicting methods on a subset of proteins that have accumulated experimental annotations between the submission deadline and the evaluation time. CAFA provides an independent and rigorous assessment of the current state of the art, thus leveling the playing field, highlighting successes, revealing bottlenecks, and offering a forum for the exchange of ideas in protein science. Here, we report the results of the fourth CAFA experiment (CAFA4). RESULTS: CAFA4 featured the participation of 148 methods from 70 research groups on a total of 46,205 unique proteins over a 5-year annotation accumulation phase, the longest in any CAFA. In a comparison across CAFA2-CAFA4 methods, the prediction of Gene Ontology (GO) terms has clearly improved across all three GO aspects and traditional evaluation settings. While not achieving the first rank, several CAFA2 and CAFA3 methods featured in the top ten methods in many evaluations, suggesting that earlier methods still hold relevance. The performance is weaker in the newly introduced "partial knowledge" evaluation category (proteins with experimental annotations before submission deadline that gained additional annotations in the same GO aspect during the annotation accumulation phase), highlighting the need for a new class of methods. The rankings of the methods were stable over the years in traditional evaluation settings, but less so in the new partial knowledge evaluation. Overall, the field continues to progress with some influx of new participants. Sustained efforts will be necessary to substantially advance it.

Journal Article↗
PubMed1992

Uterine technetium-99m mercaptoacetyltriglycine and diethylene triamine penta-acetic acid uptake in the scintigraphic evaluation of transplanted kidneys.

An anuric 35-year-old woman with a renal transplant underwent serial renal scintigraphy studies to screen the kidney function. A hypervascular pelvic mass in the region of the bladder was identified during technetium-99m mercaptoacetyltriglycine (MAG3) and also during 99mTc diethylene triamine penta-acetic acid (DT-PA) scintigraphy. She was in the secretory phase of the uterine cycle during the study and had no gynaecological problem to explain the radioactivity accumulation. The accumulation of 99mTc-MAG3 mimicking the bladder was considered as uterine activity. To our knowledge, this is the first case of uterine visualization with 99mTc-MAG3.

Adult↗
PubMed1993

The potential for avermectins to affect wildlife.

Avermectin residues in the dung from treated livestock are detrimental to dung insects. Rare insects could be put at risk by the use of avermectins, especially those which breed exclusively in the dung of the herbivores on which avermectins are used. Livestock dung is an important feeding habitat for a number of vertebrate species. The potential for direct poisoning of vertebrates through the accumulation of avermectins in the body, after consumption of invertebrates containing residues, would, on present knowledge, appear to be limited, but should not be disregarded. The use of avermectins may also indirectly affect some species of vertebrate by depleting the quality and quantity of important food resources. The effects of any reduction in invertebrate food in livestock dung would be expected to be especially severe if it occurred at critical times for the vertebrates, such as during the breeding season or when newly independent young animals were foraging and fending for themselves. Insects that develop in livestock dung therefore have important, additional roles in the ecology of pasture-lands, other than aiding dung degradation processes. It is essential that these other roles are taken into account when any assessment of the environmental consequences of using avermectins in livestock is being made.

Animal Feed↗
PubMed1994

A new method for delivering radioactive cytotoxic agents in solid cancers.

PURPOSE: Therapeutic agents such as monoclonal antibodies, radiopharmaceuticals, and radioactive growth factors are limited in effectiveness due to the inability to deposit significant quantities of the agents and for limited periods of time in solid cancer. A new technique based on knowledge of the pathophysiology of solid tumors allows for significant concentration of these agents to accumulate and for a prolonged period of time, thus allowing interaction with the tumor for potentially increased effectiveness. METHODS AND MATERIALS: Three agents have been studied: 131I antiferritin monoclonal antibody, colloidal 32P chromic phosphate, and 131I transferrin. The time required for maximal tumor uptake was determined in vitro in tissue culture and was 10 min, 25 min, and 40 min, respectively. The new method of in vivo tumor infusion consisted of a direct intratumoral injection of macroaggregated albumin (MAA) 10,000 particles, followed by the radioactive agents under study. Tumors were infused in vivo using the new technique and compared to intratumoral infused controls. In the instance of radiolabeled antiferritin antibody, intraperitoneal administration and intratumoral infusion were compared to the new technique. In the other two instances, intratumoral infusion was compared to the new method. RESULTS: In all instances the direct vascular blockade caused by MAA led to greater deposition of the agent under study for at least 24 h. These results were clinically applied with MAA followed by 32P colloidal chromic phosphate and were consistent with the experimental findings. CONCLUSION: A new technique is described that may be carried out in the experimental laboratory and clinic by direct tumor infusion of macroaggregated albumin (MAA), followed by other radioactive agents that will remain localized in solid cancers and will allow for high tumor dose deposition for potentially increased therapeutic efficacy.

Animals↗
PubMed2006

Altered auditory feedback and the treatment of stuttering: a review.

UNLABELLED: Several authors have suggested that devices delivering altered auditory feedback (AAF) may be a viable treatment for adults and children who stutter. This paper reviews published, peer reviewed journal papers from the past 10 years that investigate the effect of AAF during different speaking conditions, tasks and situations. A review of that literature indicates that considerable experimental evidence and limited Phase 1 treatment outcome evidence has been accumulated about the effect of AAF on the speech of people who stutter. However, critical knowledge about the effect of AAF during conversational speech and in everyday speaking situations is missing. Knowledge about how to determine the correct levels of AAF for individuals, and the characteristics of those likely to benefit from AAF, also needs to be established. At present there is no reason to accept a recent suggestion that AAF devices would be a defensible clinical option for children. In general device development and availability has occurred at a faster pace than clinical trials research. EDUCATIONAL OBJECTIVES: After reading this paper readers should be able to: (1) describe what altered auditory feedback is and common ways the speech signal is altered in stuttering; (2) describe the effects of AAF on the speech of adults who stutter; (3) provide a critical analysis of the literature in the area of AAF and stuttering.

Acoustic Stimulation↗
PubMed2000

Reduced glutathione oxidation ratio and 8 ohdG accumulation by mild ischemic pretreatment.

A critical role of oxidative stress has been implicated in ischemic brain damage. Mild ischemic pretreatment and/or synthesis of heat shock proteins (HSPs) has been suggested to protect against oxidative brain damage. However, experimental support of this suggestion have proven to be difficult partly because sensitive indices to assess oxidative consequences of ischemic brain damage were few. In this study, we have attempted to establish biochemical assay systems to quantitate oxidative brain damage following ischemia. We produced experimental brain ischemia in the Mongolian gerbil (Meriones unguiculatus) and examined the hippocampus for ischemic brain damage. The results obtained from ischemic gerbil hippocampus demonstrated that oxidative brain damage can be quantitated by determining glutathione oxidation ratio together with the accumulation of the oxidative DNA damage product, 8-hydroxy-2'-deoxyguanosine (8 ohdG). Our results also demonstrated a role for mild ischemic pretreatment and synthesis of HSPs against oxidative brain damage. We showed that mild 2-min ischemic pretreatment reduced the degree of both glutathione oxidation ratio and 8 ohdG accumulation in gerbil hippocampus subsequent to 10 min ischemic challenge. We also showed that the accumulation of HSP70 was closely associated with the reduction of oxidative brain damage. To our knowledge, this is the first report to investigate glutathione redox states and oxidative DNA damage levels to evaluate a protective role of mild ischemic pretreatment and HSP synthesis following brain ischemia. Our data validate the previous suggestions and provide new additional data that argue for the protective role of mild ischemic pretreatment and HSP70 synthesis against oxidative brain damage.

8-Hydroxy-2'-Deoxyguanosine↗
PubMed1991

Molecular anatomy of the blood-brain barrier as defined by immunocytochemistry.

This review outlines the recent developments and improvements of our knowledge concerning the molecular composition of the BBB as revealed by immunocytochemistry. Data have been accumulated which show that the BBB exhibits a specific collection of structural and metabolic properties which are also found in tight transporting epithelia. This conclusion is substantiated by (i) the implementation of antibodies which recognize proteins of non-BBB origin, to show that these biochemical markers and the functions that they represent are localized in the BBB endothelium; and (ii) the characterization of target molecules to which polyclonal or monoclonal antibodies which have been generated to epitopes of the BBB endothelium or brain homogenates. According to these data the protein assemblies comprising the phenotypical appearance of the BBB can therefore be defined by the particular selection as well as topological expression of common epithelial antigens, rather than the expression of BBB-unique molecular species. In this respect the immunocytochemical data corroborate the physiological assumption that the BBB possesses the character of a specific polarized epithelium. Attention is also given to the description of developmental expression of BBB-related immunomarkers. By collecting the data from different sources we introduce a classification of the BBB marker proteins according to their developmental appearance. Three groups of proteins are classified with respect to their sequential expression around the time of BBB closure: Phase E (early) markers which appear before BBB closure, phase I (intermediate) markers which are expressed at the time of BBB tightening, and phase L (late) markers which are detectable after the closure of the BBB. Such a scheme may to be useful in better defining the maturation process of BBB, which apparently is not a momentary event in brain development, but rather consists of a temporally sequenced process of hierarchically structured gene expression which finally define the molecular properties of the BBB. This process continues even after parturition, especially with regard to the achievement of immunological properties of the mature BBB. By examining the developmental spatio-temporal expression of different BBB markers we conclude that the mechanisms governing the pattern of BBB maturation are not limited to the interactions occurring between glial and endothelial cells. We therefore suggest a heuristic model in a triangular interrelationship that includes differentiation effects of neurons on glia and of glia cells on the BBB endothelium.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed2000

Coronary microcirculation: physiology and pharmacology.

Coronary microvessels play a pivotal role in determining the supply of oxygen and nutrients to the myocardium by regulating the coronary flow conductance and substance transport. Direct approaches analyzing the coronary microvessels have provided a large body of knowledge concerning the physiological and pharmacological characteristics of the coronary circulation, as has the rapid accumulation of biochemical findings about the substances that mediate vascular functions. Myogenic and flow-induced intrinsic vascular controls that determine basal tone have been observed in coronary microvessels in vitro. Coronary microvascular responses during metabolic stimulation, autoregulation, and reactive hyperemia have been analyzed in vivo, and are known to be largely mediated by metabolic factors, although the involvement of other factors should also be taken into account. The importance of ATP-sensitive K(+) channels in the metabolic control has been increasingly recognized. Furthermore, many neurohumoral mediators significantly affect coronary microvascular control in endothelium-dependent and -independent manners. The striking size-dependent heterogeneity of microvascular responses to all of these intrinsic, metabolic, and neurohumoral factors is orchestrated for optimal perfusion of the myocardium by synergistic and competitive interactions. The regulation of coronary microvascular permeability is another important factor for the nutrient supply and for edema formation. Analyses of collateral microvessels and subendocardial microvessels are important for understanding the pathophysiology of ischemic hearts and hypertrophied hearts. Studies of the microvascular responses to drugs and of the impairment of coronary microvessels in diseased conditions provide useful information for treating microvascular dysfunctions. In this article, the endogenous regulatory system and pharmacological responses of the coronary circulation are reviewed from the microvascular point of view.

Animals↗
PubMed2001

The diluted aqueous solvation of carbohydrates as inferred from molecular dynamics simulations and NMR spectroscopy.

The purpose of this paper is to review our understanding of the dilute hydration (aqueous solvation) behaviour of disaccharide compounds. To this end we discuss and scrutinize the results that have been obtained for the three model disaccharides: maltose, sucrose and trehalose from experimental NMR studies and from theoretical molecular dynamics studies in explicit aqueous solutions. The focus is on the description of molecular hydration features that will influence macroscopic entities such as diffusion and relaxation: residence times of hydration waters, hydration numbers and hydration densities. The principles of molecular dynamics simulation are briefly outlined while a detailed presentation is given of the key features that characterise hydration: the solvation of the glycosidic linkage, the radial hydration of the solute, the water density anisotropy around the solute, the residential behaviour of water molecules in the periphery of the solute, and rotational and translational diffusion coefficients. With respect to the use of NMR in characterising the structure and dynamics of the hydration, the hydrodynamic theory of rotational and translational diffusion of biomolecules as well as the use of pulse field gradient spin echo experiments are briefly presented. The NMR-defined rotational diffusion coefficients (D(r)) and the experimentally determined translational diffusion (D(t)) coefficients are reported for 4% (w/w) solutions of sucrose, trehalose and maltose. These results are compared with theoretical data obtained from molecular dynamics simulations of sucrose, trehalose and maltose under identical conditions (concentration, temperature, etc.). With our present level of knowledge we can propose that although carbohydrates share a number of hydration characteristics, evidence is accumulating in support of the notion that it is not the amount or overall hydration but rather the detailed individual carbohydrate-water interaction that is likely to determine carbohydrate structure and functionality.

Carbohydrate Conformation↗
PubMed2001

Molecular pathology of pituitary adenomas.

A great deal of knowledge about anterior pituitary development, the pathogenesis of pituitary tumor and pituitary tumor progression has accumulated during the past decade. The role of multiple genes and gene products in pituitary development and the relationship of these genes to postnatal pituitary function and pituitary tumor development are being actively explored. Recent studies indicate that genes important in pituitary development do not contribute to pituitary tumorigenesis. However, mutations and other genetic alterations in these genes often lead to pituitary hypofunction. Many oncogenes and tumor suppressor genes that contribute to pituitary tumorigenesis have been described. There is a growing body of evidence showing that cellular and molecular changes in cyclins and cyclin-dependent kinase inhibitors contribute to pituitary tumorigenesis. Finally, recent comparative genomic hybridization studies show that many more genes that are important in pituitary tumorigenesis and tumor progression have yet to be discovered.

Adenoma↗