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At least 235 records · Page 13Linked to original sources

PubMed1988

Development of substance P-containing neurons in the central nervous system in mice: an immunocytochemical study.

The embryonic development of substance P (SP) in the central nervous system (CNS) of mice has been studied with the use of peroxidase antiperoxidase (PAP) immunocytochemistry. Immature SP-positive cells initially appear at embryonic day 12 (E12) in the epithalamus and in a column of cells extending from the myelencephalon throughout the length of the neural tube. By E13, SP-positive cells appear in the amygdaloid nuclear complex, the bed nucleus of the stria terminalis, and in the caudal medulla. Fibers are first detected in the stria terminalis at this age. Over the next 48 hours, a plethora of SP-positive cells appears throughout the CNS, notably in the septal area, diagonal band nucleus, piriform cortex, accumbens nucleus, hypothalamus, rostral striatum, superior and inferior colliculi, intercollicular nucleus, substantia nigra, interpeduncular nucleus, vestibular nuclei, spinal nucleus of the trigeminal, and the nucleus of the tractus solitarii. Subsequently, SP-positive neurons and fibers increase in number and staining intensity except in the medullary raphe where the apparent number of SP-positive neurons decreases after E16. Whereas the pattern of SP staining is quite similar in mice and rats, the time of initial detection of SP-like immunoreactivity in specific nuclei is 1-4 days earlier in mice than that reported in rats with different antisera.

Aging↗

PubMed2006

Current topics in smectic liquid crystal research.

Interest in the smectic liquid-crystalline state of matter received a substantial boost with the discovery by Meyer in the mid-1970s that a chiral smectic C (SmC*) phase exhibits a spontaneous electric polarization, and with the subsequent demonstration by Clark and Lagerwall of the surface-stabilized SmC* ferroelectric liquid crystal at the beginning of the 1980s. Since then, chiral smectic phases and their plethora of polar effects have dominated the research in this field, which today has reached a mature state where the first commercial microdisplay applications are now shipping in millions-per-year quantities. In this Review we discuss some of the topics of highest interest in current smectic liquid crystal research, and address application-relevant research (de Vries-type tilting transitions without defect generation and high-tilt antiferroelectric liquid crystals with perfect dark state) as well as more curiosity-driven research (the nature and origin of the chiral smectic C subphases and their intermediate frustrated states between ferro- and antiferroelectricity).

Journal Article↗

PubMed1980

An optical model for fluorescence of mammalian sperm in flow cytometry.

When flat sperm heads that have been stained to fluorescence are examined in a flow cytometer, unexpectedly, skewed pulse height distributions are obtained despite the apparent homogeneity of the samples. This anomaly has been ascribed to an optical artifact that arises when the cells are oriented in flow. We have extended our model for fluorescent scattering to spheroids and here explore some aspects for oblate spheroids which serve to model sperm heads. Although computational limitations have restricted these studies to oblate spheroids about 1.5 micrometer in diameter and an eccentricity of 0.1, the results clearly show effects of particle size, shape, optical properties and particularly of orientation on the differential scattering cross-sections. This plethora of information contained in the fluorescent signals may suggest further experiments.

DNA↗

PubMed2005

Transgenes as screening tools to probe and manipulate the zebrafish genome.

The zebrafish, originally an object of study as an inexpensive and prolific vertebrate embryological model with a plethora of genetic tricks, has over the past decade moved to large-scale chemical mutagenesis and recently came of age as a high throughput transgenic model with a sequenced genome nearing completion. Insertional mutagenesis, gene trapping and enhancer detection are all contributing to the increasing speed with which research in this biomedical model is progressing. We review here some of the recent developments in the emerging field of zebrafish developmental genomics and transgenesis.

Animals↗

PubMed2001

Why do cells have multiple error-prone DNA polymerases?

Recent years have witnessed the emergence of a plethora of so-called novel DNA polymerases in both eukaryotic and prokaryotic cells. Many of these DNA polymerases are characterized by poor replicational fidelity and low processivity, and are devoid of 3' --> 5' exonuclease activity. This article describes the discovery of these error-prone polymerases and what is known about their biological function.

Animals↗

PubMed2002

Oligodendrocytes express an alpha/beta-interferon-susceptible Mx gene: molecular characterization of the encoded protein.

Interferons (INFs) are cytokines that exert a plethora of biological activities by interacting with receptors and inducing the synthesis of effector proteins. One such effector is an antiviral protein called Mx, widely distributed among vertebrates. Mx proteins belong to the superfamily of large GTPases, which includes dynamins, products of the Drosophila shibire gene, the yeast Vps1p, and others. Oligodendrocytes (OLGs) synthesize, assemble, and maintain myelin in the central nervous system. In an effort to identify genes implicated in establishing a myelinogenic phenotype, we isolated a 2,494 bp cDNA that encodes a protein of 654 amino acids, which are 95% identical to ovine Mx (from endometrium of pregnant sheep) and 83% similar to human MxA. Cultured OLGs express the mRNA and protein. We present structural features of this protein and speculate on the origin of its induction and the functional significance of its presence in OLGs. The finding that OLGs express an IFN-susceptible protein raises interesting possibilities in light of the evidence that beta-IFN is therapeutically beneficial for the treatment of multiple sclerosis.

Amino Acid Sequence↗

PubMed2004

Myelin-, reactive glia-, and scar-derived CNS axon growth inhibitors: expression, receptor signaling, and correlation with axon regeneration.

Axon regeneration is arrested in the injured central nervous system (CNS) by axon growth-inhibitory ligands expressed in oligodendrocytes/myelin, NG2-glia, and reactive astrocytes in the lesion and degenerating tracts, and by fibroblasts in scar tissue. Growth cone receptors (Rc) bind inhibitory ligands, activating a Rho-family GTPase intracellular signaling pathway that disrupts the actin cytoskeleton inducing growth cone collapse/repulsion. The known inhibitory ligands include the chondroitin sulfate proteoglycans (CSPG) Neurocan, Brevican, Phosphacan, Tenascin, and NG2, as either membrane-bound or secreted molecules; Ephrins expressed on astrocyte/fibroblast membranes; the myelin/oligodendrocyte-derived growth inhibitors Nogo, MAG, and OMgp; and membrane-bound semaphorins (Sema) produced by meningeal fibroblasts invading the scar. No definitive CSPG Rc have been identified, although intracellular signaling through the Rho family of G-proteins is probably common to all the inhibitory ligands. Ephrins bind to signalling Ephs. The ligand-binding Rc for all the myelin inhibitors is NgR and requires p75(NTR) for transmembrane signaling. The neuropilin (NP)/plexin (Plex) Rc complex binds Sema. Strategies for promoting axon growth after CNS injury are thwarted by the plethora of inhibitory ligands and the ligand promiscuity of some of their Rc. There is also paradoxical reciprocal expression of many of the inhibitory ligands/Rc in normal and damaged neurons, and NgR expression is restricted to a limited number of neuronal populations. All these factors, together with an incomplete understanding of the normal functions of many of these molecules in the intact CNS, presently confound interpretive acumen in regenerative studies.

Animals↗

PubMed2005

Tissue plasminogen activator and glial function.

Tissue plasminogen activator (tPA) is the only FDA-approved treatment of thrombotic stroke and is a major parenchymal serine protease in the brain. However, it has been implicated in a plethora of brain pathologies, raising concern about its use as a safe therapeutic. tPA is thought to regulate physiological processes that entail tissue remodeling and plasticity, purportedly due to its ability to initiate the degradation of extracellular matrix proteins and possibly other substrates. Understanding the physiological role(s) of tPA promises to both elucidate important aspects of brain function and improve the available therapies for neurological disease. In this context, the effects of tPA on glial cells, mainly microglial cells, but also astrocytes and Schwann cells, appear to be of particular importance, given the increasing awareness of the significance of glia in brain physiology and pathology

Animals↗

PubMed2006

Sulfatide is essential for the maintenance of CNS myelin and axon structure.

Galactocerebroside (GalC) and sulfatide are abundant myelin lipids. In mice incapable of synthesizing these lipids, myelin is thin and regionally unstable and exhibits several subtle structural abnormalities. Although galactolipid-null mice have been beneficial in the analysis of galactolipid function, it has not been possible to differentiate between the functions of GalC and sulfatide with these mice alone. In the present work, we have analyzed a murine model that forms normal levels of GalC but is incapable of synthesizing sulfatide. By comparing a plethora of morphological features between the galactolipid-null and the sulfatide-null mice, we have begun to differentiate between the specific functions of these closely related lipids. The most striking difference between these two mutants is the reduction of myelin developmental abnormalities (e.g., redundant and uncompacted myelin sheaths) in young adult sulfatide-null mice as compared with the galactolipid-null animals. Although sulfatide appears to play a limited role in myelin development, this lipid is essential for myelin maintenance, as the prevalence of redundant, uncompacted, and degenerating myelin sheaths as well as deteriorating nodal/paranodal structure is increased significantly in aged sulfatide-null mice as compared with littermate wildtype mice. Finally, we show that the role played by sulfatide in CNS maintenance is not limited to the myelin sheath, as axonal caliber and circularity are normal in young adult mutant mice but are significantly altered in aged sulfatide-null animals.

Aging↗

PubMed2002

Something old, something new, something borrowed, something blue: a framework for the marriage of health econometrics and cost-effectiveness analysis.

Economic evaluation is often seen as a branch of health economics divorced from mainstream econometric techniques. Instead, it is perceived as relying on statistical methods for clinical trials. Furthermore, the statistic of interest in cost-effectiveness analysis, the incremental cost-effectiveness ratio is not amenable to regression-based methods, hence the traditional reliance on comparing aggregate measures across the arms of a clinical trial. In this paper, we explore the potential for health economists undertaking cost-effectiveness analysis to exploit the plethora of established econometric techniques through the use of the net-benefit framework - a recently suggested reformulation of the cost-effectiveness problem that avoids the reliance on cost-effectiveness ratios and their associated statistical problems. This allows the formulation of the cost-effectiveness problem within a standard regression type framework. We provide an example with empirical data to illustrate how a regression type framework can enhance the net-benefit method. We go on to suggest that practical advantages of the net-benefit regression approach include being able to use established econometric techniques, adjust for imperfect randomisation, and identify important subgroups in order to estimate the marginal cost-effectiveness of an intervention.

Baltimore↗

PubMed2004

Exploring interactions between rat hepatocytes and nonparenchymal cells using gene expression profiling.

Cocultivation of primary hepatocytes with a plethora of nonparenchymal cells (from within and outside the liver) has been shown to support hepatic functions in vitro. Despite significant investigation into this phenomenon, the molecular mechanism underlying epithelial-nonparenchymal interactions in hepatocyte cocultures remains poorly understood. In this study, we present a functional genomic approach utilizing gene expression profiling to isolate molecular mediators potentially involved in induction of liver-specific functions by nonparenchymal cells. Specifically, primary rat hepatocytes were cocultivated with closely related murine fibroblast cell types (3T3-J2, NIH-3T3, mouse embryonic fibroblasts) to allow their classification as "high," "medium," or "low" inducers of hepatic functions. These functional responses were correlated with fibroblast gene expression profiles obtained using Affymetrix GeneChips. Microarray data analysis provided us with 17 functionally characterized candidate genes in the cell communication category (cell surface, extracellular matrix, secreted factors) that may be involved in induction of hepatic functions. Further analysis using various databases (i.e., PubMed, GenBank) facilitated prioritization of the candidates for functional characterization. We experimentally validated the potential role of two candidates in our coculture model. The cell surface protein, neural cadherin (N-cadherin), was localized to hepatocyte-fibroblast junctions, while adsorbed decorin up-regulated hepatic functions in pure cultures as well as cocultures with low-inducing fibroblasts. In the future, identifying mediators of hepatocyte differentiation may have implications for both fundamental hepatology and cell-based therapies (e.g., bioartificial liver devices). In conclusion, the functional genomic approach presented in this study may be utilized to investigate mechanisms of cell-cell interaction in a variety of tissues and disease states.

Animals↗

PubMedDate not supplied

Privatization and the allure of franchising: a Zambian feasibility study.

Efforts to privatize portions of the health sector have proven more difficult to implement than had been anticipated previously. One common bottleneck encountered has been the traditional organizational structure of the private sector, with its plethora of independent, single physician practices. The atomistic nature of the sector has rendered many privatization efforts difficult, slow and costly-in terms of both organizational development and administration. In many parts of Africa, in particular, the shortages of human and social capital, and the fragile nature of legal institutions, undermine the appeal of privatization. The private sector is left with inefficiencies, high prices and costs, and a reduced effective demand. The result is the simultaneous existence of excess capacity and unmet need. One potential method to improve the efficiency of the private sector, and thereby enhance the likelihood of successful privatization, is to transfer managerial technology--via franchising--from models that have proven successful elsewhere. This paper presents a feasibility analysis of franchizing the successful Bolivian PROSALUD system's management package to Zambia. The assessment, based on PROSALUD's financial model, demonstrates that technology transfer requires careful adaptation to local conditions and, in this instance, would still require significant external assistance.

Efficiency, Organizational↗

PubMed2002

A double-blind, placebo-controlled, randomized trial of Ginkgo biloba extract EGb 761 in a sample of cognitively intact older adults: neuropsychological findings.

There appears to be an absence of large-scaled clinical trials that have examined the efficacy of Ginkgo biloba extract on the neuropsychological functioning of cognitively intact older adults. The importance of such clinical research appears paramount in light of the plethora of products containing Ginkgo biloba that are currently being widely marketed to predominantly cognitively intact adults with claims of enhanced cognitive performances. The purpose of this research was to conduct the first known, large-scaled clinical trial of the efficacy of Ginkgo biloba extract (EGb 761) on the neuropsychological functioning of cognitively intact older adults. Two hundred and sixty-two community-dwelling volunteers (both male and female) 60 years of age and older, who reported no history of dementia or significant neurocognitive impairments and obtained Mini-Mental State Examination total scores of at least 26, were examined via a 6-week, randomized, double-blind, fixed-dose, placebo-controlled, parallel-group, clinical trial. Participants were randomly assigned to receive either Ginkgo biloba extract EGb 761(n = 131; 180 mg/day) or placebo (n = 131) for 6 weeks. Efficacy measures consisted of participants' raw change in performance scores from pretreatment baseline to those obtained just prior to termination of treatment on the following standardized neuropsychological measures: Selective Reminding Test (SRT), Wechsler Adult Intelligence Scale-III Block Design (WAIS-III BD) and Digit Symbol-Coding (WAIS-III DS) subtests, and the Wechsler Memory Scale-III Faces I (WMS-III FI) and Faces II (WMS-III FII) subtests. A subjective Follow-up Self-report Questionnaire was also administered to participants just prior to termination of the treatment phase. Analyses of covariance indicated that cognitively intact participants who received 180 mg of EGb 761 daily for 6 weeks exhibited significantly more improvement on SRT tasks involving delayed (30 min) free recall (p < 0.04) and recognition (p < 0.01) of noncontextual, auditory-verbal material, compared with the placebo controls. The EGb 761 group also demonstrated significantly greater improvement on the WMS-III FII subtest assessing delayed (30 min) recognition (p < 0.025) of visual material (i.e. human faces), compared with the placebo group. However, based on the significant difference (p < 0.03) found between the two groups' pretreatment baseline scores on the WMS-III FII, this result should be interpreted with caution. An examination of the participants' subjective ratings of their overall abilities to remember by treatment end on the Follow-up Self-report Questionnaire also revealed that significantly more (p = 0.05) older adults in the EGb 761 group rated their overall abilities to remember by treatment end as 'improved' compared with the placebo controls. Overall, the results from both objective, standardized, neuropsychological tests and a subjective, follow-up self-report questionnaire provided complementary evidence of the potential efficacy of Ginkgo biloba EGb 761 in enhancing certain neuropsychological/memory processes of cognitively intact older adults, 60 years of age and over.

Aged↗

PubMed2006

Hepatocyte growth factor activation inhibitors (HAI-1 and HAI-2) regulate HGF-induced invasion of human breast cancer cells.

Hepatocyte growth factor (HGF) plays a plethora of roles in cancer metastasis and tumour growth. The interaction between tumour cells and their surrounding stromal environment is a crucial factor regulating tumour invasion and metastasis. Stromal fibroblasts are the main source of HGF in the body, and release HGF as an inactive precursor (pro-HGF). HGF activator (HGFA), matriptase, urokinase-type plasminogen activator and hepsin are the main factors responsible for converting pro-HGF into active HGF. HAI-1 and HAI-2 are 2 novel Kunitz-type serine protease inhibitors that regulate HGF activity through inhibition of HGFA, matriptase and hepsin action. Recent studies demonstrate that HAI-1 and HAI-2 may also potently inhibit a number of other pro-metastatic serine proteases and therefore have direct bearing on the spread of tumours. Our study examined the potential of these HAI's to suppress the influence of HGF and regulate cancer metastasis. We generated a retroviral expression system that induced HAI expression in a human fibroblast cell line. Forced expression of either HAI-1 or HAI-2 in these fibroblasts resulted in a dramatic decrease in the production of bioactive hepatocyte growth factor (HGF). This reduction in HGF activity subsequently suppressed HGF's metastatic influence on breast cancer cells. To further assess the anti-cancer properties of HAI-1 and HAI-2 we generated recombinant HAI proteins. These recombinant HAI proteins possessed the ability to potently quench HGF activity. We also demonstrate that these recombinant HAI's suppressed fibroblast-mediated breast cancer invasion. An additional ribozyme transgenes study revealed that elimination of HAI-1 and HAI-2 expression, in an MDA-MB-231 breast cancer cell line, significantly enhanced the migratory, proliferative and invasive nature of these breast cancer cells. Overall, our data demonstrates the important roles of HAI-1 and HAI-2 in cancer metastasis, and reveals that these serine protease inhibitors display strong therapeutic potential.

Animals↗

PubMed1993

Mechanical stretch rapidly activates multiple signal transduction pathways in cardiac myocytes: potential involvement of an autocrine/paracrine mechanism.

It is well known that external load plays a critical role in determining cardiac muscle mass and its phenotype, but little is known as to how mechanical load is transduced into intracellular signals regulating gene expression. To address this question we analyzed the 'mechano-transcription' coupling process using an in vitro model of load-induced cardiac hypertrophy, in which a stretch of rat cardiac myocytes, grown on a deformable substrate, causes a rapid induction of immediate-early genes followed by growth (hypertrophic) response. We report here that cell stretch rapidly activates a plethora of second messenger pathways, including tyrosine kinases, p21ras, mitogen-activated protein (MAP) kinases, S6 kinases (pp90RSK), protein kinase C, phospholipase C, phospholipase D, and probably the phospholipase A2 and P450 pathways. In contrast, the cAMP pathway is not activated significantly by stretch. The signals generated by these second messengers appear to converge into activation of the p67SRF-p62TCF complex via the serum response element, causing induction of c-fos. The stretch response may involve an autocrine or paracrine mechanism, because stretch-conditioned medium, when transferred to non-stretched myocytes, mimicked the effect of stretch. These results indicate that mechanical load causes rapid activation of multiple second messenger systems, which may in turn initiate a cascade of hypertrophic response of cardiac myocytes.

Animals↗

PubMed2002

Fluorescence emission-based detection and diagnosis of malignancy.

Over the past decades, laser use in medicine has expanded from its initial application as a light-based scalpel to a plethora of clinical uses, ranging from surgical treatment through composite polymerization, dental ablation, vision correction, and skin resurfacing to diverse diagnostic modalities. Recently, the concept of light-based diagnostics and therapy has come under investigation. Low light intensities are used to excite endogenous or exogenous fluorophores, some of which have characteristic fluorescence emissions in pathological tissues. Thus, premalignancy and malignancy potentially can be detected and diagnosed. Photosensitized superficial lesions can subsequently be destroyed selectively by using higher intensities of laser light. The application of fluorescence emission-based detection and diagnosis of precancer and cancer is reviewed, based on its application to the oral cavity-the author's primary anatomical area of expertise. This approach is justified as the same principles apply throughout the human body; to any area accessible to the clinician either directly or by some sort of fiber-optic probe.

Animals↗

PubMed2006

Regulation of the p53 transcriptional activity.

In response to various stresses, p53 is rapidly activated and transcriptionally regulates a number of target genes by which p53 modulates a variety of cellular activities. The transcriptional activity of p53 is delicately regulated by a plethora of cellular factors, independently or synergistically, in multiple ways in order to achieve a specific response. This article reviewed the role of the basal transcriptional machinery, co-activators, and co-repressors involved in p53-dependent transcription, and the underlying mechanism by which the p53 transcriptional activity is regulated. We also discussed some potentially interesting questions and future directions in the field.

Animals↗

PubMed1993

Effects of electromagnetic field exposure on gene transcription.

Exposure of whole animals, isolated tissues, and cells to electromagnetic fields of various characteristics has resulted in a substantial literature detailing a wide range of effects at the morphological, physiological, biochemical, and molecular levels. In recent years, considerable effort has been devoted to defining a mechanism by which electromagnetic fields can couple to biological systems and generate this plethora of effects. As a consequence, there has been a growing interest in electromagnetic field-induced alterations in gene expression. Key studies are discussed which indicate that exposure of several cell types to electromagnetic fields that differ in waveform, amplitude, and frequency induced general changes in gene transcription. Moreover, exposure of T-lymphoblastoid cells to a 60 Hz sinusoidal magnetic field altered the transcription of genes encoding c-fos, c-jun, c-myc, and protein kinase C. Future studies in this area should focus on independent replication of key studies and identification of which events in the signal transduction pathways leading to gene transcription are altered by electromagnetic field exposure.

Animals↗