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At least 253 records · Page 14Linked to original sources
PubMed2003

Virally encoded chemokines and chemokine receptors in the role of viral infections.

Large DNA viruses such as pox- and in particular herpesviruses are notorious in their ability to evade the immune system and to be maintained in the general population. Based on the accumulated knowledge reviewed in this study it is evident that important mechanisms of these actions are the acquisition and modification of host-encoded chemokines and chemokine receptors. The described viral molecules leave nothing to chance and have thoroughly and efficiently corrupted the host immune system. Through this process viruses have identified key molecules in antiviral responses by their inhibition of these or potent ways to alter an efficient antiviral response to a weak Th2-driven response. Examples here are the chemokine scavenging by US28, attractance of Th2 cells and regulatory cells by vMIP1-3 and the selective engaging of CCR8 by MC148. Important insights into viral pathology and possible targets for antiviral therapies have been provided by UL33, UL78 and in particular ORF74 and the chances are that many more will follow. In HHV8 vMIP-2 and the chemokine-binding proteins potent anti-inflammatory agents have been provided. These have already had their potential demonstrated in animal models and may in their native or modified forms represent useful therapies in humans.

Animals↗
PubMedDate not supplied

Orosomucoid polymorphism in Finns, Swedes and Swedish Saamis.

Genetic polymorphism of orosomucoid (ORM) was studied by isoelectric focusing and immunoblotting in Finns, Swedes and Swedish Saamis. The ORM2 locus was found to be monomorphic in all three ethnic groups. In the Swedish sample the frequency of the ORM1*2 allele (0.414) was within the range found in other European populations, whereas Finns (0.282) and Saamis (0.210) showed significantly lower ORM1*2 frequencies. The extremely low ORM1*2 frequency in the Saamis further underlines the genetic uniqueness of this population. The ORM1*2 frequency in Saamis resembles those in Asiatic Mongoloid populations, but this is unlikely to reflect an Asiatic influence, since the accumulated knowledge on genetic markers in the Saamis show no unequivocal evidence for an Asiatic influence in this population.

Adult↗
PubMed2005

Muscle sympathetic nerve activity averaged over 1 minute parallels renal and cardiac sympathetic nerve activity in response to a forced baroreceptor pressure change.

BACKGROUND: Despite the accumulated knowledge of human muscle sympathetic nerve activity (SNA) as measured by microneurography, whether muscle SNA parallels renal and cardiac SNAs remains unknown. METHOD AND RESULTS: In experiment 1, muscle (microneurography, tibial nerve), renal, and cardiac SNAs were recorded in anesthetized rabbits (n=6) while arterial pressure was changed by intravenous bolus injections of nitroprusside (3 microg/kg) followed by phenylephrine (3 microg/kg). In experiment 2, the carotid sinus region was vascularly isolated in anesthetized, vagotomized, and aorta-denervated rabbits (n=10). The 3 SNAs were recorded while intracarotid sinus pressure was increased stepwise from 40 to 160 mm Hg in 20-mm Hg increments maintained for 60 seconds each. Muscle SNA averaged over 1 minute was well correlated with renal (r=0.96+/-0.01, mean+/-SE) and cardiac (r=0.96+/-0.01) SNAs in experiment 1 (baroreflex closed-loop condition) and also with renal (r=0.97+/-0.01) and cardiac (r=0.97+/-0.01) SNAs in experiment 2 (baroreflex open-loop condition). CONCLUSIONS: Muscle SNA averaged over 1 minute parallels renal and cardiac SNAs in response to a forced baroreceptor pressure change.

Animals↗
PubMed1997

Reflections on metapsychology, theoretical coherence, hermeneutics, and biology.

Unable to correlate clinical findings with contemporary neurophysiology, Freud tried to anchor psychoanalysis within biology through a speculative metapsychology. Recently, epistemological objections have led to abandonment of his proposals qua scientific theory, although many still use them metaphorically. Others deny the need for any general theory of mental functions. Some theorists would espouse a hermeneutic basis for psychoanalysis, outside the boundaries of biology; they purport to confine their purview to mental contents but often use concepts based on metapsychological assumptions. Because the meanings of such contents are difficult to determine, their interpretation should be "constructed" in collaboration with analysands. By contrast, trained observers may reliably collect psychobiological data, accumulating knowledge of cognition, affectivity, communication, and the regulation of behavior--matters Freud encompassed via the economic and structural viewpoints. Hence analytic theory should be correlated with the findings of semiotics, cognitive psychology, and brain science. The hermeneutic focus on dynamics and genetics overlooks crucial data, such as the occurrence of trauma, leading to confusion about processes of pathogenesis, working through, and structural change. These and other biological phenomena (such as functional deficits and repetitive enactments) call for interventions beyond interpreting mental contents; improvement depends on learning better to process these contents. Change implies gradual establishment of alternative neural pathways; this does not automatically follow insight. Hence psychoanalysis must deal with intrapsychic phenomena beyond subjectivity. Intrapsychic conflicts represent efforts to ward off archaic mentality (primitive thought processing). Theories divorced from neurocognitive considerations encourage the theoretical fiction that analysands possess an "intact ego."

Biology↗
PubMed1999

Modeling the individual determinants of research utilization.

Despite more than two decades of investigation, our accumulated knowledge about what influences nurses' use of research is underdeveloped. This study's objectives were to develop and test a series of structural equation models that included individual factors believed to influence research utilization. Estimates of the models were obtained using maximum likelihood estimation. Model fit was assessed by examining chi-square, the adjusted goodness of fit index, and the standardized residuals. Within a simple model that permitted only direct effects and controlled for instrumental, conceptual, and persuasive research utilization, 3 of 26 concepts exerted significant effects on research utilization. These were a positive attitude toward research, belief suspension, and in-services attended. These results support the assertion that our descriptive body of research on the determinants of research utilization is underdeveloped, limiting our ability to design and test effective strategies to increase the use of research findings in nursing practice.

Attitude of Health Personnel↗
PubMed2000

Negotiating with helping systems: an example of grounded theory evolving through emergent fit.

A strength of substantive grounded theories is that they are modifiable. Yet, little attention is given in the research literature to the evolution of grounded theories through the process of emergent fit. In this article, emergent fit is discussed, and the evolution of the theoretical understanding of relationships with helping systems is provided as an example. In a feminist grounded-theory study of women's caring, emergent fit with existing inductive research on health care relationships resulted in a framework of negotiating, which includes four strategies: reframing responsibility, becoming an expert, harnessing resources, and taking on more. This explanatory model demonstrates how the use of emergent fit can avoid the generation of isolated theories and contribute to knowledge accumulation by producing a substantive theory with wider applicability.

Adaptation, Psychological↗
PubMed2006

Characterization of HIV-1 subtype C envelope glycoproteins from perinatally infected children with different courses of disease.

BACKGROUND: The causal mechanisms of differential disease progression in HIV-1 infected children remain poorly defined, and much of the accumulated knowledge comes from studies of subtype B infected individuals. The applicability of such findings to other subtypes, such as subtype C, remains to be substantiated. In this study, we longitudinally characterized the evolution of the Env V1-V5 region from seven subtype C HIV-1 perinatally infected children with different clinical outcomes. We investigated the possible influence of viral genotype and humoral immune response on disease progression in infants. RESULTS: Genetic analyses revealed that rapid progressors (infants that died in the first year of life) received and maintained a genetically homogeneous viral population throughout the disease course. In contrast, slow progressors (infants that remained clinically asymptomatic for up to four years) also exhibited low levels variation initially, but attained higher levels of diversity over time. Genetic assessment of variation, as indicated by dN/dS, showed that particular regions of Env undergo selective changes. Nevertheless, the magnitude and distribution of these changes did not segregate slow and rapid progressors. Longitudinal trends in Env V1-V5 length and the number of potential N-glycosylation sites varied among patients but also failed to discriminate between fast and slow progressors. Viral isolates from rapid progressors and slow progressors displayed no significant growth properties differences in vitro. The neutralizing activity in maternal and infant baseline plasma also varied in its effectiveness against the initial virus from the infants but did not differentiate rapid from slow progressors. Quantification of the neutralization susceptibility of the initial infant viral isolates to maternal baseline plasma indicated that both sensitive and resistant viruses were transmitted, irrespective of disease course. We showed that humoral immunity, whether passively acquired or developed de novo in the infected children, varied but was not predictive of disease progression. CONCLUSION: Our data suggest that neither genetic variation in env, or initial maternal neutralizing activity, or the level of passively acquired neutralizing antibody, or the level of the de novo neutralization response appear to be linked to differences in disease progression in subtype C HIV-1 infected children.

Amino Acid Substitution↗
PubMed2005

Adeno-associated virus: from defective virus to effective vector.

The initial discovery of adeno-associated virus (AAV) mixed with adenovirus particles was not a fortuitous one but rather an expression of AAV biology. Indeed, as it came to be known, in addition to the unavoidable host cell, AAV typically needs a so-called helper virus such as adenovirus to replicate. Since the AAV life cycle revolves around another unrelated virus it was dubbed a satellite virus. However, the structural simplicity plus the defective and non-pathogenic character of this satellite virus caused recombinant forms to acquire centre-stage prominence in the current constellation of vectors for human gene therapy. In the present review, issues related to the development of recombinant AAV (rAAV) vectors, from the general principle to production methods, tropism modifications and other emerging technologies are discussed. In addition, the accumulating knowledge regarding the mechanisms of rAAV genome transduction and persistence is reviewed. The topics on rAAV vectorology are supplemented with information on the parental virus biology with an emphasis on aspects that directly impact on vector design and performance such as genome replication, genetic structure, and host cell entry.

Adenoviridae↗
PubMed2003

ICU cornerstone: high frequency ventilation is here to stay.

With favourable and extensive experience in the neonatal intensive care unit (ICU) and the recent positive experience in the adult ICU, high-frequency ventilation has become a valuable alternative to conventional ventilation in acute lung injury. To arrive at this point, physicians' understanding of the characteristics and kinetics of acute lung injury had to become more distinct, and it was necessary to merge accumulated knowledge from experience with high-frequency ventilation in the neonatal population and that with conventional ventilation in adults. However, this now calls for a better designed clinical trial in the adult population that combines the three most important concepts for lung protection: early intervention (before acute respiratory distress syndrome is established); optimal lung recruitment; and careful avoidance of lung over-distention over the entire period of mechanical ventilation.

Child↗
PubMed2006

The role of epithelial cells in the initiation and perpetuation of autoimmune lesions: lessons from Sjogren's syndrome (autoimmune epithelitis).

Sjögren's syndrome (SS) is a chronic autoimmune disease affecting epithelial tissues. Exocrine glands are the primary target and their functional impairment comes as a result of immune attack of epithelial cells of the affected organs (autoimmune epithelitis). In this interplay, the role of the epithelial cell is pivotal. Extensive data point to an intrinsically activated status. Moreover, the epithelial cells possess all the features needed in order to act as non-professional antigen presenting cells. Through apoptosis and exosomes release endocellular antigens contributing to tolerance breakdown. In addition, produce cytokines and chemokines that recruit lymphocytes in the immunopathogenic lesion. Herein, we review all the aforementioned aspects of the epithelial activity that lead to the perpetuation of the lesion as well as the probable viral factors for the intrinsic activation. Finally, we propose a model for SS pathogenesis that integrates the knowledge accumulated during the last decade.

Autoimmune Diseases↗
PubMed2004

REST and peace for the neuronal-specific transcriptional program.

Despite a genetic homogeneity, cells in multicellular organisms are structurally and functionally heterogeneous. The diversity of cell phenotypes exists due to differential transcriptional programs precisely regulated by specific nuclear factors and induced upon differentiation. The differences in gene expression programs arise during development and become heritable during cell proliferation. Over the last few years, research has focused on three molecular mechanisms that mediate epigenetic phenomena: DNA methylation, histone modification, and formation of specialized nuclear domains or territories. All of these processes are dynamic and tightly linked to the organism's development. Here we review advances in understanding the significance of epigenetic mechanisms in the establishment and maintenance of the specialized transcriptional program. We project the accumulated knowledge onto the delineation of the molecular mechanisms by which central nervous system-specific genes are expressed in the nervous system and repressed in other tissues.

Animals↗
PubMed2004

Somatostatin receptor targeting for tumor imaging and therapy.

Somatostatin receptors and their ligands constitute the prototype targeting system for contrast-enhanced detection and radiotherapy of cancer. Radiolabeled synthetic analogs of somatostatin have been successfully used in routine molecular imaging of primary gastroenteropancreatic neuroendocrine tumors and their metastases for more than 15 years. Likewise, analog conjugates for radiation therapy have been developed and have been under clinical trial for several years. The vast amount of knowledge accumulated by both basic and clinical science has made the somatostatin/somatostatin receptor system a popular model for new targeting strategies in imaging and therapy. Among those, the use of near-infrared fluorescent dye-peptide conjugates for the detection of tumors by endoscopy, mammography, or intraoperative imaging is one of the most promising. This article reviews recent developments in the field and discusses concepts for receptor-targeted molecular imaging and therapy.

Animals↗
PubMed1989

The two-factor model of self-reported mood: a cross-cultural replication.

The cross-cultural stability of a two-factor model of self-reported mood was studied in Israel. Sixty women and 25 men filled out a 58-adjective Mood Check List, everday for 45 consecutive days. Replicatory factor analyses demonstrated that the two-factor model of mood is applicable to both Israeli men and women and that this structure is consistent across American and Israeli cultures. Three implications of these findings are discussed. Replication of this structure in a diversified and unique culture, such as Israel, coupled with a previous replication in Japan (Watson, Clark, & Tellegen, 1984), is interpreted as lending considerable support to the assertion that this model of mood is cross-culturally consistent. Theoretical formulations and empirical findings derived and discovered in the U.S. can now be employed in planning and interpreting mood studies in Israel. The results of such studies can be incorporated within the general body of knowledge accumulating on this topic in the U.S.

Adult↗
PubMed2001

The new human tissue kallikrein gene family: structure, function, and association to disease.

The human tissue kallikrein gene family was, until recently, thought to consist of only three genes. Two of these human kallikreins, prostate-specific antigen and human glandular kallikrein 2, are currently used as valuable biomarkers of prostatic carcinoma. More recently, new kallikrein-like genes have been discovered. It is now clear that the human tissue kallikrein gene family contains at least 15 genes. All genes share important similarities, including mapping at the same chromosomal locus (19q13.4), significant homology at both the nucleotide and protein level, and similar genomic organization. All genes encode for putative serine proteases and most of them are regulated by steroid hormones. Recent data suggest that at least a few of these kallikrein genes are connected to malignancy. In this review, we summarize the recently accumulated knowledge on the human tissue kallikrein gene family, including gene and protein structure, predicted enzymatic activities, tissue expression, hormonal regulation, and alternative splicing. We further describe the reported associations of the human kallikreins with various human diseases and identify future avenues for research.

Amino Acid Sequence↗
PubMed2004

[Diagnostic standards of von Willebrand disease].

Von Willebrand disease (VWD) is caused by quantitative and/or qualitative defects of the von Willebrand factor (VWF), a multimeric high molecular glycoprotein. Typically, it affects the primary haemostatic system, which is reflected by a mucocutaneous bleeding tendency simulating a functional platelet defect. The VWF promotes its function in two ways: It promotes platelet adhesion to the injured vessel wall under conditions of high shear forces and it functions as carrier for factor VIII in plasma. Due to its complexity diagnosis of VWD is one of the most challenging of coagulation disorders. The stepwise diagnosis of VWD includes patient's and family history, orientating procedures (bleeding time, filter tests, platelet count, aPTT), confirmatory tests (VWF:Ag, VWF:RCo, VIII:C) and tests for final classification (VWF:CB, RIPA, multimeric analysis, bWF:FVIIIB, platelet VWF). Accumulating knowledge of the different clinical phenotypes and their pathophysiological basis was translated into a classification scheme that differentiated between quantitative and qualitative defects by means of quantitative and functional parameters and by analyzing the electrophoretic pattern of VWF multimers. The advent of molecular techniques provided the opportunity for genotype/phenotype studies which recently helped not only to elucidate or confirm important functions of VWF and the steps of its posttranslational processing but also many disease causing defects.

Diagnosis, Differential↗
PubMed2003

Murine embryonic stem cell in vitro differentiation: applications to the study of vascular development.

The present review summarizes knowledge accumulated during the last decade concerning in vitro endothelial differentiation from embryonic stem (ES) cells. There is now growing evidence that ES cells may provide a powerful model system to determine the cellular and molecular mechanisms of vascular development. ES cells differentiate into the endothelial lineage by successive maturation steps recapitulating in vivo events observed in the embryo. Further maturation of ES-derived embryoid bodies either in three dimensional gels or in confrontation cultures with tumor spheroids can also provide a model of physiological or tumoral angiogenesis. The data obtained from experimental in vitro differentiation of genetically modified mouse ES cells highlight the potential and the complementarity of this model system to in vivo gene knock out studies. We also consider and discuss some of the potential applications of ES cell technology in vascular biology for future directions in basic research and medicine, by manipulation of differentiation and the generation of cell populations for analysis and transplantation for therapeutic use.

Animals↗
PubMed1995

[ATP-sensitive potassium channel and hormone/neuropeptide].

ATP-sensitive potassium channels (KATP) are the ion channels which are closely associated with cellular metabolism. A number of chemical compounds which block KATP facilitate the release of hormones or neuropeptides. For example, KATP-blocking agents such as antidiabetic sulfonylureas and imidazolines stimulate insulin secretion from pancreatic beta-cells by decreasing KATP activity. On the other hand, so-called potassium channel openers, KATP-activating drugs which constitute a chemically diverse group of compounds, inhibit growth hormone secretion from anterior pituitary cells and release of gamma-aminobutylic acid from substantia nigra. Several endogenous substances also modulate release of hormone or neuropeptide by affecting KATP activity. Acetylcholine and histamine stimulate the release of endothelium-derived hyperpolarizing factor, which activates KATP in the plasma membrane of vascular smooth muscle cells. Both galanin and somatostatin inhibit insulin release from pancreatic beta-cells by opening KATP through the activation of G-protein. Glucagon-like peptide-1[7-36], which stimulates insulin secretion by indirectly blocking KATP in beta-cells, shows antidiabetic effects in patients with non-insulin-dependent diabetes mellitus. Endosulphine, an endogenous inhibitor of KATP, stimulates insulin secretion from pancreatic beta-cells. Accumulating knowledge of the modulation and function of KATP would help our understanding of the regulation and physiological role of hormones and neuropeptides.

Adenosine Triphosphate↗
PubMed2002

Clodronate: mechanisms of action on bone remodelling and clinical use in osteometabolic disorders.

Clodronate (CI2MBP) is a non-aminated bisphosphonate that inhibits bone resorption. Studies on the mechanisms of action of this molecule on bone metabolism have been limited and only recently has information on the molecular machinery that underlies its effects on the bone remodelling process become available. Pharmacological and clinical studies have demonstrated the effectiveness of clodronate in the treatment of postmenopausal osteoporosis and in all conditions of excessive bone resorption, such as Paget's disease, hypercalcaemia of malignancy and osteolytic metastases. Clodronate is the only bisphosphonate currently available on the market for both oral and parenteral administration. Treatment with clodronate via intramuscular administration of doses of 100 mg/week has shown significant effects on bone mineral density after 6 months in patients with postmenopausal osteoporosis and these effects are maintained 3 years after the start of the treatment. In a recent controlled clinical study, a significant increase in bone mineral density was observed, associated with a 46% reduction in the incidence of vertebral fractures. However, most relevant studies have been small, unblinded and short-term and have not systematically examined the effects of the dose and dosing intervals on bone mineral density and markers of bone turnover. Ongoing controlled clinical studies may offer answers regarding potential use of clodronate in osteoporosis and also about dosage of intermittent administration. This review summarises the accumulated knowledge in the mechanisms of action of clodronate on bone remodelling. Moreover, the clinical trials on the use of clodronate in metabolic bone diseases are described in-depth. We believe that this work will help to better focus on the need for more research on a compound which has potential applications in prevention and therapy of osteoporosis. However, studies that demonstrate an effect on the rate of fractures are needed before any recommendation can be made.

Antimetabolites↗