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At least 217 records · Page 12Linked to original sources
PubMed1995

Spontaneous acceptance of rat liver allografts is associated with an early downregulation of intragraft interleukin-4 messenger RNA expression.

Liver allografts are not rejected in the fully incompatible Lewis-RT1(1) (LEW) to blood group D Agouti-RT1a (DA) rat strain combination despite an early infiltration by recipient mononucleated cells that initially display a phenotype, an ability to respond to interleukin-2 (IL-2) and donor-specific cytotoxicity indistinguishable from that observed in the rejected, DA to LEW combination. To further analyze the mechanism of this tolerance, we have compared in these two combinations, as well as in syngeneic grafts and in normal livers, the presence of intrahepatic cytokine transcripts (IL-1 alpha, IL-2, IL-4, IL-6, IL-10, tumor necrosis factor [TNF]-alpha, TNF-beta, and transforming growth factor [TGF]-beta) by a semiquantitative polymerase chain reaction (PCR) or by northern-blotting. In normal livers or syngeneic grafts, IL-1 alpha, TNF-beta, and TGF-beta were the only cytokines detected by these methods. The levels of all cytokine transcripts were increased in allogeneic grafts. Expression of cytokine transcripts was very similar in the two allogeneic strain combinations except IL-4, which was expressed at a much lower level in the nonrejected strain than in the rejected strain from day 2 onward. We conclude that selective downregulation of IL-4 gene expression is associated with, and a potential mediator of, the induction of tolerance in this model.

Acute-Phase Reaction↗
PubMed2006

An association rule mining-based methodology for automated detection of ischemic ECG beats.

Currently, an automated methodology based on association rules is presented for the detection of ischemic beats in long duration electrocardiographic (ECG) recordings. The proposed approach consists of three stages. 1) Preprocessing: Noise is removed and all the necessary ECG features are extracted. 2) Discretization: The continuous valued features are transformed to categorical. 3) CLASSIFICATION: An association rule extraction algorithm is utilized and a rule-based classification model is created. According to the proposed methodology, electrocardiogram (ECG) features extracted from the ST segment and the T-wave, as well as the patient's age, were used as inputs. The output was the classification of the beat as ischemic or not. Various algorithms were tested both for discretization and for classification using association rules. To evaluate the methodology, a cardiac beat dataset was constructed using several recordings of the European Society of Cardiology ST-T database. The obtained sensitivity (Se) and specificity (Sp) was 87% and 93%, respectively. The proposed methodology combines high accuracy with the ability to provide interpretation for the decisions made, since it is based on a set of association rules.

Arrhythmias, Cardiac↗
PubMed1988

Role of CD8 (Lyt-2) in cytotoxic T-cell function. Analysis of variants of a cytotoxic T-cell clone with reduced Lyt-2 expression.

The role of CD8 (Lyt-2) in the function of a long-term cytotoxic T-cell (CTL) clone (Cl96) was analysed. Previous studies had shown that C196 cells utilize the alpha beta T-cell receptor and depend on Lyt-2 to recognize and lyse P815 mastocytoma target cells. Recognition is H-2Kd-restricted, presumably involving a P815 specific antigenic structure. Here we analyse a number of variants selected from Cl96 that have reduced or virtually abolished expression of Lyt-2, alone or in combination with other deficiencies. We studied the ability of these variant cells to lyse either P815, a process requiring both specific antigen recognition and triggering of cytolytic function, or to lyse the anti-CD3 hybridoma 145-2C11, a process that requires the triggering of cytolytic function only. The results shows that in the case or a permanently activated CTL effector cell such as Cl96, Lyt-2 is required for antigen recognition but is not essential for the triggering of cytotoxicity.

Animals↗
PubMed1978

Dyslexia revisited. A review.

Specific developmental dyslexia, a condition characterized by reduced reading, spelling, and writing abilities combined with normal intellectual capacity, has challenged geneticists and 'environmentalists.' Although most of the strikingly controversial results can be traced to differences concerning diagnostic decision-making, there are many hints of a genetic contribution. Twin studies and extensive pedigree analysis substantiate this view, but it is too early to infer a definite mode of inheritance from the available data.

Child↗
PubMed1995

Tonic inhibition originates from synapses close to the soma.

Central neurons are subject to a tonic barrage of randomly occurring spontaneous inhibitory events (mIP-SCs) resulting from the action potential-independent release of gamma-aminobutyric acid (GABA). Do the terminals making synapses onto somatic versus dendritic sites, which arise from specific populations of interneurons, differ in their ability to generate mIPSCs? We have combined the techniques of whole-cell patch-clamp recording and computational simulation to demonstrate that in granule cells of the dentate gyrus, most of the action potential-independent inhibition taking place as mIPSCs originates from proximal sites. Indeed, removal of the bulk (> 50%) of the dendritic tree did not change the characteristics of mIPSCs. These results are consistent with a functional segregation of GABAergic terminals synapsing at proximal versus distal portions of central neurons. Thus, proximal GABAergic terminals are responsible for tonic inhibition targeted at the soma.

Action Potentials↗
PubMed2006

Changes in protein synthesis during thermal adaptation of Propionibacterium freudenreichii subsp. shermanii.

Dairy propionibacteria are present in Graviera Kritis, a traditional Gruyère-type cheese made without added propionic starter. Ten isolated strains were identified by a combination of SDS-PAGE, species-specific PCR and according to their ability to ferment lactose. They were all found to belong to the Propionibacterium freudenreichii subsp. shermanii species. Because of the stressing Gruyère technology, which includes cooking at 52 to 53 degrees C their thermotolerance was investigated at 55 degrees C. Thermotolerant and thermosensitive strains were clearly discriminated. Interestingly, the reference strain CIP 103027 belongs to the sensitive subset. One sensitive strain, ACA-DC 1305 and one tolerant, ACA-DC 1451, were selected for further study and compared to CIP 103027. For the sensitive strains ACA-DC 1305 and CIP 103027, heat pre-treatment at 42 degrees C conferred thermoprotection of cells at the lethal temperature of 55 degrees C, while there was less effect on the tolerant ACA-DC 1451. No cross-protection of salt-adapted cells against heat stress was observed for none of the strains. Differential proteomic analysis revealed distinct but overlapping cell responses to heat stress between sensitive and tolerant strains. Thermal adaptation upregulated typical HSPs involved in protein repair or turnover in the sensitive one. In the tolerant one, a distinct subset of proteins was overexpressed, whatever the temperature used, in addition to HSPs. This included enzymes involved in propionic fermentation, amino acid metabolism, oxidative stress remediation and nucleotide phosphorylation. These results bring new insights into thermoprotection in propionibacteria and the occurrence of divergent phenotypes within a same subspecies.

Adaptation, Physiological↗
PubMed1999

Gender, psychosocial factors and the use of medical services: a longitudinal analysis.

Many researchers have reported gender differences in levels of reported symptoms, morbidity, mortality and medical care utilization, but the debate continues about the underlying causes of these differences. Some have argued that women use more medical services because they are more sensitive to symptoms and interested in health, while others believe that women's greater service utilization arises from the fact that women experience more morbidities than do men. To date, these questions have not been studied prospectively. Using data from a household interview survey carried out in 1970-1971 and linked to 22 years of health services utilization records, we explored the effects of gender, self-reported health status, mental and physical symptom levels, health knowledge, illness behaviors and health concerns and interest on the long-term use of health services. After controlling for the aforementioned factors, female gender remained an independent predictor of higher utilization over the 22-year period studied, and psychosocial and health factors measured at the initial interview predicted service use even 19-22 years later. Controlling for factors identified as likely causes of gender-related differences in healthcare utilization, gender remains an important predictor of medical care use before and after removing sex-specific utilization. In addition, the consistent predictive ability of attitudinal and behavioral factors, combined with the finding that health knowledge did not predict utilization, indicates that efforts to help patients assess their service needs should target the attitudinal and behavioral factors that vary with gender, rather than health-related knowledge alone.

Adolescent↗
PubMed2003

Collection of trace amounts of DNA/mRNA molecules using genomagnetic nanocapturers.

The collection and then the separation of rare DNA/mRNA targets with single-base mismatches in a complex matrix is critically important in human disease diagnostics, gene expression studies, and gene profiling. The major result of this work is the development and application of a novel genomagnetic nanocapturer (GMNC) for the collection, separation, and detection of trace amounts of DNA/RNA molecules with one single-base difference. The GMNC is constructed by bioconjugating molecular beacon DNA probes onto magnetic nanoparticle surfaces. We have successfully applied the GMNC in artificial buffer solution samples and in cancer cell samples, both containing different proteins and random DNA sequences. Our method has three distinctly useful features: highly efficient collection of trace amount of DNA/mRNA samples down to femtomolar (10(-15) M) concentrations; excellent ability to differentiate single-base-mismatched DNA/mRNA samples by combining the exceptional specificity of molecular beacons and the separation power of magnetic nanoparticles; and real-time monitoring and confirmation of the collected gene products. The newly developed genomagnetic nanocapturers will be highly useful for the collection of trace amounts of DNA/mRNA targets in a variety of sample sources in forensic, medical, and biotechnological fields.

Actins↗
PubMed1997

Value of somatostatin receptor scintigraphy: a prospective study in gastrinoma of its effect on clinical management.

BACKGROUND & AIMS: Recently [111In-DTPA-D-Phe1]-octreotide was approved for somatostatin receptor scintigraphy (SRS) of gastroenteropancreatic tumors. SRS and other tumor localization methods can be time consuming, expensive, and involve patient inconvenience. The role of SRS in comparison to other tumor localization modalities remains undefined because the relative effects of these methods on management have not been studied. The aim of this study was to determine whether SRS alters clinical management in Zollinger-Ellison syndrome. METHODS: One hundred twenty-two consecutive patients were studied prospectively. Each patient was assigned to one of five different clinical categories. Conventional imaging studies (ultrasonography, computerized tomography, magnetic resonance image, angiography, and bone scan) were performed, and the management was proposed. SRS was then performed. Clinical management was reassessed, and whether SRS altered management was determined based on six criteria. RESULTS: SRS was superior to any single imaging study. SRS altered management in 47% overall and in 22%-60% of patients in the five different clinical categories. Primary tumor localization and clarification of equivocal localization results from conventional studies were the principal reasons for altering management. SRS was equally useful in patients with or without metastatic liver disease. CONCLUSIONS: Because of the ability of SRS to alter clinical management combined with its superior sensitivity, high specificity, simplicity, and cost-effectiveness, SRS should be the initial imaging modality for patients with gastrinomas.

Adult↗
PubMed2003

Apoptosis and plastic surgery.

Apoptosis, or programmed cell death, is a phenomenon that is integral to development and cellular homeostasis. In the last decade, many of the essential molecules and pathways that control this phenomenon have been elucidated. Because apoptosis is involved in almost all physiologic and pathologic processes, the understanding of its regulation has significant clinical ramifications. This article reviews the basic understanding of programmed cell death in terms of the effector molecules and pathways. Areas of interest to plastic surgeons are reviewed as they pertain to apoptosis. These areas include allotransplantation, craniofacial and limb development, flap survival, wound healing, stem cell science, and physiologic aging. These topics have not yet been studied extensively in the context of cell death. In this review article, other related and more comprehensively studied scientific areas are used to extrapolate their relevance to apoptosis. Apoptosis is an increasingly better understood process. With the knowledge of how programmed cell death is controlled, combined with the improved ability to effectively perform genetic manipulation and to design specific chemical approaches, apoptosis is gaining clinical relevance. In the next few years, practical clinical breakthroughs will help the medical community to understand the phenomenon of apoptosis and how it relates to the needs of patients.

Aging↗
PubMed1986

Positron emission tomography in normal aging and Alzheimer's disease.

Age differences are not found for the regional cerebral metabolic rate for glucose (rCMR glc) measured with positron emission tomography (PET) with 18F-2-deoxy-D-glucose, in healthy subjects at rest and with reduced sensory stimulation. Furthermore, measures of cognitive function are not correlated with resting rCMR glc in healthy subjects. In patients with presumptive Alzheimer's disease (AD), regional cerebral blood flow is reduced throughout the brain in relation to the severity of dementia, whereas regional reductions in rCMR glc are correlated with neuropsychometric deficits subserved by those regions. Right-left asymmetries in rCMR glc appear early in AD and are correlated with appropriate right-left asymmetries in language as compared to visuo-constructive abilities. Thus, PET, when combined with neuropsychological measures, can be used to examine specific cerebral function changes during the course of AD.

Adult↗
PubMed2000

Transforming activity of receptor tyrosine kinase tyro3 is mediated, at least in part, by the PI3 kinase-signaling pathway.

Protein tyrosine phosphorylation is an integral part of cytokine-induced proliferation and differentiation of hematopoietic cells. The authors previously reported cloning and characterization of the receptor tyrosine kinase Tif, also termed Tyro3. Using the yeast 2-hybrid technology, they recently identified that the p85 subunit of phosphatidylinositol 3-kinase (PI3 kinase) interacted with the cytoplasmic domain of Tyro3. On treatment with epidermal growth factor (EGF), NIH3T3 cells expressed EGFR/Tyro3 (a fusion receptor with the extracellular domain from epidermal growth factor receptor and the transmembrane and cytoplasmic domains from Tyro3), and EGFR/Tyro3 was rapidly phosphorylated on tyrosine residues. The interaction between Tyro3 and p85 was also confirmed by glutathione S-transferase (GST) pull-down experiments. Co-immunoprecipitation followed by Western blot analysis revealed that PI3 kinase was associated with and phosphorylated by the activated Tyro3. Tyro3-associated PI3 kinase exhibited an enhanced kinase activity. In addition, EGF treatment of EGFR/Tyro3-expressing cells led to enhanced phosphorylation of Akt, a downstream component of PI3 kinase. Treatment of NIH3T3 cells expressing a full length of rat Tyro-3, but not NIH3T3 cells, with protein S also resulted in phosphorylation of Akt. Soft agar colony assays showed that the addition of EGF to EGFR/Tyro3-transfected cells, but not to the parental NIH3T3 cells, resulted in a concentration-dependent increase in the formation of anchorage-independent colonies. Tyro3-mediated transformation of NIH3T3 cells was significantly blocked by wortmannin, a PI3 kinase-specific inhibitor. Results of these combined studies strongly suggested that the oncogenic transforming ability of Tyro3 was mediated at least in part by the PI3 kinase pathway. (Blood. 2000;95:633-638)

3T3 Cells↗
PubMedDate not supplied

Acute pancreatitis associated with administration of a nitric oxide synthase inhibitor in tumor-bearing dogs.

BACKGROUND: Nitric oxide synthase (NOS) inhibitors have been investigated as potential cytotoxic agents to treat tumors lacking p53 function. Furthermore, their ability to reduce tumor blood flow can be combined with drugs that are specifically designed to kill cells that are hypoxic or to improve temperatures during local heat (hyperthermia) treatment of tumors. This paper reports the unexpected development of acute pancreatitis in two tumor-bearing pet dogs that were treated with the NOS inhibitor, NG-nitro-L-arginine methyl ester (L-NAME) during administration of local hyperthermia. METHODS: Prior to the use of L-NAME in tumor-bearing dogs, purpose-bred beagles were studied. Following induction of inhalation anesthesia, local hyperthermia was applied to either normal thigh muscle (beagles) or tumors (tumor-bearing dogs). Once a thermal steady state was achieved, L-NAME was administered and temperature monitoring continued. Animals were observed after treatment for evidence of toxicity. RESULTS: The beagles tolerated the treatment well, with no side effects noted either clinically or by routine CBC or blood chemistry analyses. In contrast, the first two tumor-bearing dogs accrued onto the phase I study developed acute pancreatitis in the immediate post-treatment period which necessitated hospitalization and intensive care. The trial was stopped. Both dogs had intercurrent risk factors which predisposed them to development of pancreatitis, although neither had a history of symptoms of pancreatitis at the time the hyperthermia + L-NAME treatment was given. CONCLUSIONS: We conclude that caution should be exercised when considering NOS inhibition for cancer treatment. Careful evaluation of history and health status as well as recognition of potential risk factors may be key in avoiding potentially fatal complications. This study demonstrates the value of performing potentially harmful treatments in tumor-bearing dogs prior to introduction into the human clinic.

Acute Disease↗
PubMed2002

Drug delivery systems based on sugar-macromolecule conjugates.

The specificity of carbohydrate-protein interactions can greatly outstrip that of many other ligand-binding systems; such is the enormous density of information that sugars can convey. In addition, macromolecules allow for the fine-tuning of active drug delivery through their great ability to undergo site-specific modification and their inherent physicochemical properties. Once combined, these two factors suggest that sugar-macromolecule conjugates, targeted using endogenous carbohydrate binding proteins, are a promising route to the 'magic bullet'.

Animals↗
PubMed2005

Apoptin nuclear accumulation is modulated by a CRM1-recognized nuclear export signal that is active in normal but not in tumor cells.

Tumor cell-specific activity of chicken anemia virus viral protein 3 (VP3 or apoptin) is believed to be dependent on its ability to localize in the nucleus of transformed but not of primary or nontransformed cells. The present study characterizes the signals responsible for the novel nucleocytoplasmic trafficking properties of VP3 using two isogenic tumor/nontumor cell pairs. In addition to the tumor cell-specific nuclear targeting signal, comprising two stretches of basic amino acids in the VP3 COOH terminus which are highly efficient in tumor but not in normal cells, we define the CRM1-recognized nuclear export sequence (NES) within the VP3 tumor cell-specific nuclear targeting signal for the first time. Intriguingly, the NES (amino acids 97-105) is functional in normal but not in tumor cells through the action of the threonine 108 phosphorylation site adjacent to the NES which inhibits its action. In addition, we characterize a leucine-rich sequence (amino acids 33-46) that assists VP3 nuclear accumulation by functioning as a nuclear retention sequence, conferring association with promyelocytic leukemia nuclear bodies. This unique combination of signals is the basis of the tumor cell-specific nuclear targeting abilities of VP3.

Active Transport, Cell Nucleus↗
PubMed2006

Multifunctional nanocarriers.

Currently used pharmaceutical nanocarriers, such as liposomes, micelles, nanoemulsions, polymeric nanoparticles and many others demonstrate a broad variety of useful properties, such as longevity in the blood allowing for their accumulation in pathological areas with compromised vasculature; specific targeting to certain disease sites due to various targeting ligands attached to the surface of the nanocarriers; enhanced intracellular penetration with the help of surface-attahced cell-penetrating molecules; contrast properties due to the carrier loading with various contrast materials allowing for direct carrier visualization in vivo; stimuli-sensitivity allowing for drug release from the carriers under certain physiological conditions, and others. Some of those pharmaceutical carriers have already made their way into clinic, while others are still under preclinical development. What could be seen much more rare, however, are the pharmaceutical nanocarriers combining several from the listed abilities. Long-circulating immunoliposomes capable of prolonged residence in the blood and specific target recognition represent one of few examples of this kind. At the same time, the enginnering of multifunctional pharmaceutical nanocarriers combinig several useful preoperties in one particle can significantly enhance the efficacy of many therapeutic and diagnostic protocols. This paper considers current status and possible future directions in the emerging area of multifunctional nanocarriers with primary attention on the combination of such properties as longevity, targetability, intracellular penetration and contrast loading.

Drug Carriers↗
PubMed1984

Hypothesis: the MHC-restricted T-cell receptor as a structure with two multistate allosteric combining sites.

This paper presents a dual-recognition model of the T-cell receptor that has been constructed to account for the phenomenon of MHC restriction as well as the paradoxical ability of T-cells to be both multispecific and precisely specific at the same time. In our model the combining sites for antigen and MHC are not independent as in classical dual-recognition models, but interact with each other by an allosteric mechanism. We envision a flexible receptor with combining sites for antigen and MHC that are capable of existing in a multitude of distinct complementarity states. MHC and antigen molecules act as allosteric effectors such that one ligand perturbs the conformation and therefore the specificity of the site for the other ligand. An essential feature of the model is that different MHC determinants induce different conformations at the anti-antigen site. In this way the receptor acquires multiple specificities. Within a particular complementarity state, precise recognition results from the requirement that antigen and MHC exhibit positive cooperativity in their binding to the T-cell receptor. Positive cooperativity is also the basis for MHC restriction. Reaction mechanisms are presented which describe the requirement that antigen and MHC both induce conformational changes in order to generate high-affinity binding to either ligand. As a precedent for the multistate allosteric receptor model, we discuss the properties of allosteric enzymes, especially ribonucleotide reductase, whose properties are analogous to those we have postulated for the T-cell receptor. Also discussed is the possibility that molecules such as Ly2, L3T4 and the Mls antigen, which have been found to play a role in antigen recognition, function as affinity-enhancing allosteric effectors that interact with the constant portion of the T-cell receptor.

Allosteric Site↗