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PubMed1998

[Clinical course of restenosis after carotid endarterectomy].

Angiologic and neurologic examinations, ultrasonic dopplerography were performed in 89 patients after operation of carotid endarterectomy. Period of observation was 6-182 months after operation (61 months on the average). Positive clinical effect (absence of disorders of cerebral circulation-DCC) was achieved in 91% of cases. The frequency of both repeated transitory ischemic attacks and the strokes was 9%, the best frequency being in patients with initially asymptomatic course. It was found that the degree of restenosis directly correlated with frequency of neurologic symptom development: there were no repeated DCC in normal state of the operated artery. Meanwhile DCC frequency was less than 4% in cases with the degree of restenosis less than 60% and was equal to 15.8% in more than 60% restenosis. DCC were more frequently found in occlusion of internal carotid artery. Rather favourable course of restenosis of carotid artery was also conditioned by low content of the plaques dangerous in terms of embolism. Progression of atherosclerotic damages in other parts of extracranial arteries promoted clinical manifestation of cerebral ischemia. Moreover, negative neurologic dynamics developed in 7% of the patients with restenosis less than 60%, and in 13.8% of cases with restenosis more than 60%. The conclusion was made about efficiency of carotid endarterectomy in patients with atherosclerotic damages of carotid arteries. For prevention of repeated DCC it is recommended both to perform conservative therapy after the operation and to examine dynamically the patients using ultrasonic dopplerography beginning 6 months after the operation.

Adult↗

PubMed1998

Tracking the contribution of a family medicine clerkship to the clinical curriculum.

BACKGROUND AND OBJECTIVES: Medical educators are working to articulate the objectives and measure the outcomes of medical education. In clinical training, faculty need methods to identify both the principal educational contributions of individual clerkships and how prior experiences influence student learning. METHODS: We analyzed students' perceived acquisition of clinical knowledge and skills on a 4-week, community-based family medicine clerkship. The data represent 349 third-year medical students who participated in the clerkship during a 2-year time period. Results were summarized by three different combinations of prior clerkship experiences and overall. RESULTS: Students reported gains as a result of the clerkship for the majority of medical problems and procedures. However, there were differences in the clerkship's perceived contribution depending on the timing and sequence of clinical rotations. Even when the family medicine clerkship followed all other primary care rotations, students perceived that the clerkship contributed to gains in knowledge of undifferentiated and commonly seen problems; applications of health promotion, disease prevention, and patient education; importance of family dynamics in patient care; business aspects of medical practice; and appreciation of family practice. CONCLUSIONS: The results demonstrate how a required family medicine clerkship can enhance the clinical learning that occurs on other rotations. The study also demonstrates that it is possible to track a clerkship's contribution to student development and to understand how a clerkship's role may change according to students' prior experiences.

Clinical Clerkship↗

PubMed1997

[Long-term outcome at adjacent levels of lumbar arthrodesis].

Posterolateral lumbar fusion is commonly recognized to have a significant effect upon the more proximal unfused segments. Wether these effects are clinically significant remains unclear. Long term studies with standardized follow-up are scarce. The purpose of this study was to examine the long term roentgenographic and clinical effects of posterolateral fusion upon the 3 cephalad unfused segments. The levels below a floating fusion were also examined. The factors promoting the occurrence of degenerative changes on standard or dynamic x rays were also investigated with a multivariate analysis model. 102 patients who underwent a posterolateral fusion were retrospectively reviewed with an average follow-up of 8.9 years. 39 patients (group I) were fused for low back pain caused by isthmic lysis spondylolisthesis, 15 (group II) for degenerative disc disease and 48 (group III) in addition to a posterior decompression for a lumbar spinal stenosis. Pre and postoperative standard and dynamic roentgenograms were compared in order to study: evolution of the disc space height, modifications in the angular and antero-posterior mobility, modifications in the antero-posterior displacement of the vertebral bodies. Degenerative changes were frequent. 49 per cent of the patients demonstrated a severe disc space narrowing, 30 per cent developed a degenerative spondylolisthesis, 32 per cent an angular hypermobility and 35 per cent an antero-posterior hypermobility. Only one factor was found to increase significantly the occurrence of degenerative changes: the indication of lumbar fusion. Degenerative changes were significantly more frequent in group III's patients. However, no significant correlation was found between the roentgenographic findings and the final functional results and only 8 patients required a new surgery. These results may suggest that posterolateral fusion accelerates the development of degenerative changes in adjacent discs if the fusion is performed on a degenerative spine.

Adolescent↗

PubMed1992

Role of the health professional in ending the tobacco pandemic: clinic, classroom, and community.

Physicians and other health professionals have become complacent about the tobacco pandemic, because there is a mistaken belief that the war on smoking has been won. In reality, the survival from lung cancer is little better than it was 30 years ago, and cigarettes have become the most advertised and promoted product in society. The prevalence of overall smoking in the United States has declined by only 0.5%/y during the past decade. Among certain US minority populations, the decline has been far less or nonexistent. Traditional efforts to control the tobacco pandemic have been reactive and static, whereby government agencies, schools, and health professionals provide the public with generic information about the adverse health effects of smoking. As a result of these efforts, it is assumed that individuals will act to change their behavior. In contrast, the tobacco industry is proactive and dynamic, changing its brand-name strategies through advertising and promotion. To more effectively combat tobacco use, health officials need to move beyond patient education and adopt a more active model that includes clinic-based, school-based, and community-based tobacco-control strategies. Use of humorous, satirical images as part of paid counteradvertising campaigns and proactive health education curricula should be part of a concerted effort to end the tobacco pandemic and limit the promotional influence of tobacco companies.

Consumer Advocacy↗

PubMed1997

Human monocyte ATP-induced IL-1 beta posttranslational processing is a dynamic process dependent on in vitro growth conditions.

Despite a large production capacity, freshly isolated lipopolysaccharide (LPS)-activated human monocytes release only a small percentage of their newly synthesized interleukin (IL)-1 beta into the medium. Extracellular ATP, acting via surface P2z-type purino-receptors, increases cytokine posttranslational processing. To explore whether this ATP response was affected by culture conditions, monocytes were maintained for different time periods in the absence and presence of various media components including fetal bovine and human sera and recombinant human cytokines. The ability of monocytes to produce radiolabeled pro-IL-1 beta in response to LPS and to posttranslationally process the procytokine after ATP stimulation was affected both by time in culture and by the presence of specific media components. These observations indicate that ATP's ability to promote human monocyte IL-1 beta posttranslational processing is a dynamic process that is subject to regulation by cytokines and/or growth factors. Changes in monocyte/macrophage ATP responsiveness may provide an important regulatory mechanism for the control of IL-1 biological activity in vivo.

Adenosine Triphosphate↗

PubMed2006

Mechanical stretch modulates the promoter activity of the profibrotic factor CCN2 through increased actin polymerization and NF-kappaB activation.

The connective tissue growth factor known as CCN2 is an inducible, profibrotic molecule that becomes aberrantly expressed in mechanical overload-bearing tissues. In this study, we found that CCN2 gene expression is rapidly induced in cyclically stretched bladder smooth muscle cells (SMCs) in vitro and in the detrusor muscle of a mechanically overloaded bladder in a rat model of experimental urethral obstruction. The activity of CCN2 promoter constructs, transiently transfected into cultured SMCs, was increased (up to 6-fold) by continuous cyclic stretching. Molecular analyses of the CCN2 promoter by serial construct deletions, cis-element mutagenesis, and electrophoretic mobility shift assays revealed that a highly conserved NF-kappaB binding site located within the CCN2 proximal promoter region is responsible for the activation of the promoter by stretch. Chromatin immunoprecipitation assays showed that NF-kappaB binds to the endogenous CCN2 promoter in both stretched cells and mechanically overloaded bladder tissues. Furthermore, stretch-dependent CCN2 promoter activity was significantly reduced upon inhibition of either phosphatidylinositol 3-kinase, p38 stress-activated kinase, or RhoA GTPase and was completely abolished upon inhibition of actin polymerization. Concordantly, actin polymerization was increased in either mechanically stretched cells or overloaded bladder tissues. Incubation of cultured SMCs with a cell-penetrating peptide containing the N-terminal sequence, Ac-EEED, of smooth muscle alpha-actin, altered both actin cytoskeleton organization and stretch-mediated nuclear relocation of NF-kappaB, and subsequently, it reduced CCN2 promoter activity. Thus, mechanical stretch-induced changes in actin dynamics mediate NF-kappaB activation and induce CCN2 gene expression, which probably initiates the fibrotic reactions observed in mechanical overload-associated pathologies.

Amino Acid Sequence↗

PubMed2006

Retinol modulates site-specific mobility of apo-cellular retinol-binding protein to promote ligand binding.

A fundamental question in protein science is how the inherent dynamics of a protein influence its function. If this function involves interactions with a ligand, the protein-ligand encounter has the potential to modulate the protein dynamics. This study reveals how site-specific mobility can be modulated by the ligand to facilitate high affinity binding. We have investigated the mechanism of retinol uptake by the cellular retinol-binding protein type I (CRBP) using line shape analysis of NMR signals. The highly similar structures of apo- and holo-CRBP exhibit closed conformations that seemingly offer no access to ligand, yet the protein binds retinol rapidly and with high affinity. NMR line shape analysis reveals how protein dynamics resolve this apparent paradox. An initial nonspecific encounter with the ligand induces the formation of long-lived conformers in the portal region of CRBP suggesting a mechanism how retinol accesses the cavity.

Binding Sites↗

PubMed2006

Dictyostelium myosin II mechanochemistry promotes active behavior of the cortex on long time scales.

Cell cortices rearrange dynamically to complete cytokinesis, crawlin response to chemoattractant, build tissues, and make neuronal connections. Highly enriched in the cell cortex, actin, myosin II, and actin crosslinkers facilitate cortical movements. Because cortical behavior is the consequence of nanoscale biochemical events, it is essential to probe the cortex at this level. Here, we use high-resolution laser-based particle tracking to examine how myosin II mechanochemistry and dynacortin-mediated actin crosslinking control cortex dynamics in Dictyostelium. Consistent with its low duty ratio, myosin II does not directly drive active bead motility. Instead, myosin II and dynacortin antagonistically regulate other active processes in the living cortex.

Animals↗

PubMed2001

Peculiar 2-aminopurine fluorescence monitors the dynamics of open complex formation by bacteriophage T7 RNA polymerase.

The kinetics of promoter binding and open complex formation in bacteriophage T7 RNA polymerase was investigated using 2-aminopurine (2-AP) modified promoters. 2-AP serves as an ideal probe to measure the kinetics of open complex formation because its fluorescence is sensitive to both base-unpairing and base-unstacking and to the nature of the neighboring bases. All four 2-AP bases in the TATA box showed an increase in fluorescence with similar kinetics upon binding to the T7 RNA polymerase, indicating that the TATA sequence becomes unpaired in a concerted manner. The 2-AP at -4 showed a peculiarly large increase in fluorescence upon binding to the T7 RNA polymerase. Based on the recent crystal structure of the T7 RNA polymerase-DNA complex, we propose that the large fluorescence increase is due to unstacking of the 2-AP base at -4 from the guanine at -5, during open complex formation. The unstacking may be a critical event in directing and placing the template strand correctly in the T7 RNA polymerase active site upon promoter melting for template directed RNA synthesis. Based on equilibrium fluorescence and stopped-flow kinetic studies, we propose that a fast form of T7 RNA polymerase binds promoter double-stranded DNA by a three-step mechanism. The initial collision complex or a closed complex, ED(c) is formed with a K(d) of 1.8 microm. This complex isomerizes to an open complex, ED(o1), in an energetically unfavorable reaction with an equilibrium constant of 0.12. The ED(o1) further isomerizes to a more stable open complex, ED(o2), with a rate constant around 300 s(-1). Thus, in the absence of the initiating nucleotide, GTP, the overall equilibrium constant for closed to open complex conversion is 0.5 and the net rate of open complex formation is nearly 150 s(-1).

2-Aminopurine↗

PubMed2005

Beneficial role of noise in promoting species diversity through stochastic resonance.

There is an increasing recognition that patterns in species diversity cannot be understood without reference to nonequilibrial or unstable dynamics. Recently, through a realistic ecological model that involves dispersal, we have addressed the positive role of noise in promoting species coexistence [Phys. Rev. Lett. 94, 038102 (2005)]. Here we present a physical theory to account for the main scaling law responsible for this phenomenon.

Journal Article↗

PubMed1996

Linking reengineering to revitalization.

A health care organization that embarks on reengineering without a strategy for revitalizing is courting disaster. What does it take to get reengineering right? It takes vision, unflinching commitment, new kinds of leadership and business strategies, and new behaviors to challenge the old manager-physician power dynamic. A low-cost health care provider must be able to promote trust, partnerships, and competencies that are specifically linked to accessible, cost-effective patient care.

Career Mobility↗

PubMed2003

A function for the mitochondrial chaperonin Hsp60 in the structure and transmission of mitochondrial DNA nucleoids in Saccharomyces cerevisiae.

The yeast mitochondrial chaperonin Hsp60 has previously been implicated in mitochondrial DNA (mtDNA) transactions: it is found in mtDNA nucleoids associated with single-stranded DNA; it binds preferentially to the template strand of active mtDNA ori sequences in vitro; and wild-type (rho+) mtDNA is unstable in hsp60 temperature-sensitive (ts) mutants grown at the permissive temperature. Here we show that the mtDNA instability is caused by a defect in mtDNA transmission to daughter cells. Using high resolution, fluorescence deconvolution microscopy, we observe a striking alteration in the morphology of mtDNA nucleoids in rho+ cells of an hsp60-ts mutant that suggests a defect in nucleoid division. We show that rho- petite mtDNA consisting of active ori repeats is uniquely unstable in the hsp60-ts mutant. This instability of ori rho- mtDNA requires transcription from the canonical promoter within the ori element. Our data suggest that the nucleoid dynamics underlying mtDNA transmission are regulated by the interaction between Hsp60 and mtDNA ori sequences.

Cell Division↗

PubMed2004

Dynamic balancing of the dual nature of HIF-1alpha for cell survival.

In hypoxic cells, HIF-1alpha escapes from oxygen-dependent proteolysis and binds to the hypoxia-responsive element (HRE) for transcriptional activation of target genes involved in angiogenesis and glycolysis. We recently demonstrated that the G(1) checkpoint gene p21(cip1)is activated by HIF-1alpha with a novel mechanism that involves the HIF-1alpha PAS domains to displace Myc binding from p21(cip1) promoter. This HIF-1alpha-Myc pathway may account for up- and down-regulation of other hypoxia-responsive genes that lack the HRE. Moreover, the role of HIF-1alpha in cell cycle control indicates a dual, yet seemingly conflicting, nature of HIF-1alpha: promoting cell growth and arrest in concomitance. We speculate that a dynamic balance between the two processes is achieved by a "stop-and-go" strategy to maintain cell growth and survival. Tumor cells may adopt such scheme to evade the killing by chemotherapeutic agents.

Adaptation, Physiological↗

PubMed2001

Self-organized dynamics in spatially structured populations.

Self-organization and pattern formation represent the emergence of order in temporal and spatial processes. Self-organization in population ecology is gaining attention due to the recent advances concerning temporal fluctuations in the population size of dispersal-linked subunits. We shall report that spatially structured models of population renewal promote the emergence of a complex power law order in spatial population dynamics. We analyse a variety of population models showing that self-organization can be identified as a temporal match in population dynamics among local units, and how the synchrony changes in time. Our theoretical results are concordant with analyses of population data on the Canada lynx.

Animals↗

PubMed2006

Bolaamphiphiles promote phospholipid translocation across vesicle membranes.

A series of membrane-spanning bolaamphiphiles (molecules with two hydrophilic end groups connected by a hydrophobic linker) were prepared by a modular synthetic method and evaluated for their abilities to affect the dynamics of a surrounding bilayer membrane. The goal was to determine if the bolaamphiphiles promote the translocation of phospholipids across vesicle membranes. The bolaamphiphiles were incorporated at low levels (up to 5 mol %) in vesicles composed of 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC). Inward translocation assays were performed using fluorescent, NBD-labeled phospholipid probes with phosphocholine (PC) or phosphoglycerol (PG) headgroups. The membrane-spanning bolaamphiphiles promote the translocation of both phospholipid probes in the order PG > PC, whereas shorter bolaamphiphiles (structures that must adopt a U-shape and keep both end groups in the same leaflet of the membrane), and regular amphiphiles with one hydrophilic end group, are inactive. These results are an exception to the rule-of-thumb that membrane-spanning bolaamphiphiles are inherently membrane-stabilizing molecules that inhibit all types of membrane transport.

Membranes, Artificial↗

PubMed2025

A new tool for engineering Phaeodactylum tricornutum: the METE promoter drives both high expression and B12-tuneable regulation of transgenes.

For advanced metabolic engineering strategies, it is crucial to be able to regulate transgene expression, to prevent potential deleterious effects in the host organism during growth and allow optimisation of production levels. Here, we identified vitamin B12 (cobalamin)-responsive promoters in the diatom Phaeodactylum tricornutum, a promising biotechnological chassis that readily absorbs this metabolite with minimal physiological impact. Using promoter-reporter constructs, the promoters of the cobalamin acquisition protein 1 (CBA1) and the B12-independent form of methionine synthase (METE) were shown to regulate transgene expression in a B12-dependent manner. Further characterisation of the METE promoter (PMETE) demonstrated that it exhibited significantly higher expression levels than several previously characterised promoters, but could be repressed by nanomolar amounts of B12, with a dynamic range >100-fold. Tight regulation was demonstrated by the suppression of the lethal ribonuclease, barnase at 1 μg L-1 B12. Reporter expression was doubled when PMETE was paired with its cognate terminator, compared with the widely used FCPA terminator. Promoter truncations resulted in decreased expression, but no loss of B12 regulation. A 14 nucleotide motif, present in four copies in PMETE, was found to be necessary for expression, and when fused to the constitutive FCPA promoter, enhanced expression levels. Transgenic lines expressing the heterologous diterpenoid enzyme, casbene synthase, produced casbene titres of approximately 2 mg L-1 and this was tuneable by B12. This demonstrates the utility of PMETE in efforts to establish P. tricornutum as an industrial biotechnology production platform.

Promoter Regions, Genetic↗

PubMed2004

Spindle checkpoint protein dynamics at kinetochores in living cells.

BACKGROUND: To test current models for how unattached and untense kinetochores prevent Cdc20 activation of the anaphase-promoting complex/cyclosome (APC/C) throughout the spindle and the cytoplasm, we used GFP fusions and live-cell imaging to quantify the abundance and dynamics of spindle checkpoint proteins Mad1, Mad2, Bub1, BubR1, Mps1, and Cdc20 at kinetochores during mitosis in living PtK2 cells. RESULTS: Unattached kinetochores in prometaphase bound on average only a small fraction (estimated at 500-5000 molecules) of the total cellular pool of each spindle checkpoint protein. Measurements of fluorescence recovery after photobleaching (FRAP) showed that GFP-Cdc20 and GFP-BubR1 exhibit biphasic exponential kinetics at unattached kinetochores, with approximately 50% displaying very fast kinetics (t1/2 of approximately 1-3 s) and approximately 50% displaying slower kinetics similar to the single exponential kinetics of GFP-Mad2 and GFP-Bub3 (t1/2 of 21-23 s). The slower phase of GFP-Cdc20 likely represents complex formation with Mad2 since it was tension insensitive and, unlike the fast phase, it was absent at metaphase kinetochores that lack Mad2 but retain Cdc20 and was absent at unattached prometaphase kinetochores for the Cdc20 derivative GFP-Cdc20delta1-167, which lacks the major Mad2 binding domain but retains kinetochore localization. GFP-Mps1 exhibited single exponential kinetics at unattached kinetochores with a t1/2 of approximately 10 s, whereas most GFP-Mad1 and GFP-Bub1 were much more stable components. CONCLUSIONS: Our data support catalytic models of checkpoint activation where Mad1 and Bub1 are mainly resident, Mad2 free of Mad1, BubR1 and Bub3 free of Bub1, Cdc20, and Mps1 dynamically exchange as part of the diffuse wait-anaphase signal; and Mad2 interacts with Cdc20 at unattached kinetochores.

Anaphase-Promoting Complex-Cyclosome↗

PubMed2003

GA-binding protein (GABP) and Sp1 are required, along with retinoid receptors, to mediate retinoic acid responsiveness of CD18 (beta 2 leukocyte integrin): a novel mechanism of transcriptional regulation in myeloid cells.

CD18 (beta(2) leukocyte integrin) is transcriptionally regulated in myeloid cells, but the mechanisms that increase its expression in response to retinoic acid (RA) have not been defined. The CD18 promoter was activated by RA treatment in stably transfected U937 myeloid cells. We identified a retinoic acid response element (RARE) that lies nearly 900 nucleotides upstream of the CD18 transcriptional start site that was bound by the RA receptors, retinoic acid receptor (RAR) and retinoic X receptor (RXR). This RARE accounted for one half of the RA responsiveness of CD18. However, unexpectedly, one half of the dynamic response to RA was mediated by the 96-nucleotide CD18 minimal promoter, which lacks a recognizable RARE. Binding sites for the ets transcription factor, GA-binding protein (GABP), and Sp1 were required for full RA responsiveness of both the CD18 minimal promoter and the full-length promoter. The ets sites conferred RA responsiveness on an otherwise unresponsive heterologous promoter, and RA responsiveness was directly related to the number of ets sites. The transcriptional coactivator p300/CBP physically interacted with GABP in vivo, and p300 increased the responsiveness of the CD18 promoter to RA. These studies demonstrate a novel role for non-RAR transcription factors in mediating RA activation in myeloid cells. They support the concept that transcription factors other than RARs are required for RA-activated gene expression. We hypothesize that a multiprotein complex--an enhanceosome--that includes GABP, other transcription factors, and coactivators, dynamically regulates CD18 expression in myeloid cells.

Binding Sites↗