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PubMed2002

Clonal spread of resistant pneumococci despite diminished antimicrobial use.

The effects of community-wide interventions to reduce resistance rates are poorly understood. This study evaluated the effect of reduced antimicrobial usage on the spread of penicillin-nonsusceptible pneumococci (PNSP) in four communities in Iceland. The study was performed after interventions to reduce antimicrobial usage and compared to an identical study performed 5 years before. A randomized sample of 953 children was chosen from all 2,900 1- to 6-year-old children living in four well-defined communities. The main outcome measures were nasopharyngeal carriage of PNSP and individual and community use of antimicrobials. Pneumococci were carried by 51.7% of the 743 children enrolled, and 8.1% of the pneumococci were PNSP as opposed to 8.5% in the previous study. The antimicrobial use of participants had been reduced from 1.5 to 1.1 courses/year and the overall use among children <7 years old living in the study areas from 13.6 to 11.1 defined daily dosages/1000 children per day. The prevalence of PNSP increased in the two areas furthest away from the capital area despite reduced consumption. The major risk factors for carriage of PNSP remained the same. Interventions can be effective in reducing antimicrobial use. Pandemic multiresistant clones can also spread fast in small communities with low antimicrobial use, where their appearance may be delayed compared to highly populated urban areas. Clonal spread and herd immunity are important factors to be considered in the evaluation of intervention effects.

Anti-Bacterial Agents↗
PubMed2000

Exposure at the cell surface is required for gas3/PMP22 To regulate both cell death and cell spreading: implication for the Charcot-Marie-Tooth type 1A and Dejerine-Sottas diseases.

Gas3/PMP22 is a tetraspan membrane protein highly expressed in myelinating Schwann cells. Point mutations in the gas3/PMP22 gene account for the dominant inherited peripheral neuropathies Charcot-Marie-Tooth type 1A disease (CMT1A) and Dejerine-Sottas syndrome (DSS). Gas3/PMP22 can regulate apoptosis and cell spreading in cultured cells. Gas3/PMP22 point mutations, which are responsible for these diseases, are defective in this respect. In this report, we demonstrate that Gas3/PMP22-WT is exposed at the cell surface, while its point-mutated derivatives are intracellularly retained, colocalizing mainly with the endoplasmic reticulum (ER). The putative retrieval motif present in the carboxyl terminus of Gas3/PMP22 is not sufficient for the intracellular sequestration of its point-mutated forms. On the contrary, the introduction of a retrieval signal at the carboxyl terminus of Gas3/PMP22-WT leads to its intracellular accumulation, which is accompanied by a failure to trigger cell death as well as by changes in cell spreading. In addition, by substituting the Asn at position 41 required for N-glycosylation, we provide evidence that N-glycosylation is required for the full effect on cell spreading, but it is not necessary for triggering cell death. In conclusion, we suggest that the DSS and the CMT1A neuropathies derived from point mutations of Gas3/PMP22 might arise, at the molecular level, from a reduced exposure of Gas3/PMP22 at the cell surface, which is required to exert its biological functions.

3T3 Cells↗
PubMed2001

RhoA inactivation by p190RhoGAP regulates cell spreading and migration by promoting membrane protrusion and polarity.

The binding of extracellular matrix proteins to integrins triggers rearrangements in the actin cytoskeleton by regulating the Rho family of small GTPases. The signaling events that mediate changes in the activity of Rho proteins in response to the extracellular matrix remain largely unknown. We have demonstrated in previous studies that integrin signaling transiently suppresses RhoA activity through stimulation of p190RhoGAP. Here, we investigated the biological significance of adhesion-dependent RhoA inactivation by manipulating p190RhoGAP signaling in Rat1 fibroblasts. The inhibition of RhoA activity that is induced transiently by adhesion was antagonized by expression of dominant negative p190RhoGAP. This resulted in impaired cell spreading on a fibronectin substrate, reduced cell protrusion, and premature assembly of stress fibers. Conversely, overexpression of p190RhoGAP augmented cell spreading. Dominant negative p190RhoGAP elevated RhoA activity in cells on fibronectin and inhibited migration, whereas overexpression of the wild-type GAP decreased RhoA activity, promoted the formation of membrane protrusions, and enhanced motility. Cells expressing dominant negative p190RhoGAP, but not control cells or cells overexpressing the wild-type GAP, were unable to establish polarity in the direction of migration. Taken together, these data demonstrate that integrin-triggered RhoA inhibition by p190RhoGAP enhances spreading and migration by regulating cell protrusion and polarity.

Actins↗
PubMed1994

Integrin binding and cell spreading on extracellular matrix act at different points in the cell cycle to promote hepatocyte growth.

This study was undertaken to determine the importance of integrin binding and cell shape changes in the control of cell-cycle progression by extracellular matrix (ECM). Primary rat hepatocytes were cultured on ECM-coated dishes in serum-free medium with saturating amounts of growth factors (epidermal growth factor and insulin). Integrin binding and cell spreading were promoted in parallel by plating cells on dishes coated with fibronectin (FN). Integrin binding was separated from cell shape changes by culturing cells on dishes coated with a synthetic arg-gly-asp (RGD)-peptide that acts as an integrin ligand but does not support hepatocyte extension. Expression of early (junB) and late (ras) growth response genes and DNA synthesis were measured to determine whether these substrata induce G0-synchronized hepatocytes to reenter the growth cycle. Cells plated on FN exhibited transient increases in junB and ras gene expression (within 2 and 8 h after plating, respectively) and synchronous entry into S phase. Induction of junB and ras was observed over a similar time course in cells on RGD-coated dishes, however, these round cells did not enter S phase. The possibility that round cells on RGD were blocked in mid to late G1 was confirmed by the finding that when trypsinized and replated onto FN-coated dishes after 30 h of culture, they required a similar time (12-15 h) to reenter S phase as cells that had been spread and allowed to progress through G1 on FN. We have previously shown that hepatocytes remain viable and maintain high levels of liver-specific functions when cultured on these RGD-coated dishes. Thus, these results suggest that ECM acts at two different points in the cell cycle to regulate hepatocyte growth: first, by activating the G0/G1 transition via integrin binding and second, by promoting the G1/S phase transition and switching off the default differentiation program through mechanisms related to cell spreading.

Amino Acid Sequence↗
PubMed1996

NG2 proteoglycan and the actin-binding protein fascin define separate populations of actin-containing filopodia and lamellipodia during cell spreading and migration.

The transmembrane proteoglycan NG2 is able to interact both with components of the extracellular matrix and with the actin cytoskeleton. An examination of the distribution of NG2 during cell spreading suggests that NG2 can associate with two distinct types of actin-containing cytoskeletal structures, depending on the nature of the stimulus derived from the substratum. On fibronectin-coated dishes, cell surface NG2 associates exclusively with stress fibers developing within the cell. On poly-L-lysine-coated dishes, cell surface NG2 is associated with radial processes extending from the cell periphery. Spreading on fibronectin/poly-L-lysine mixtures, as well as on matrix components such as laminin, tenascin, and type VI collagen, produces cells with mosaic characteristics, i.e., NG2 is associated with both types of structures. NG2-positive radial processes are distinct from a second population of radial structures that contain fascin. NG2-positive extensions appear to be individual self-contained units (filopodia), whereas fascin is associated with actin ribs within sheets of membrane (lamellipodia). NG2- and fascin-positive structures are often localized to opposite poles of spreading cells, suggesting a possible role for the two classes of cellular extensions in the establishment of cell polarity during morphogenesis or migration. Time lapse imaging confirms the presence of lamellipodia on the leading edges of migrating cells, while numerous filopodia are present on trailing edges.

Actins↗
PubMed2002

Ordered nucleation and spreading of silenced chromatin in Saccharomyces cerevisiae.

In Saccharomyces cerevisiae, silencing at the HM loci depends on Sir proteins, which are structural components of silenced chromatin. To explore the structure and assembly of silenced chromatin, the associations of Sir proteins with sequences across the HMR locus were examined by chromatin immunoprecipitation. In wild-type cells, Sir2p, Sir3p, and Sir4p were spread throughout and coincident with the silenced region at HMR. Sir1p, in contrast, associated only with the HMR-E silencer, consistent with its role in establishment but not maintenance of silencing. Sir4p was required for the association of other Sir proteins with silencers. In contrast, in the absence of Sir2p or Sir3p, partial assemblies of Sir proteins could form at silencers, where Sir protein assembly began. Spreading across HMR required Sir2p and Sir3p, as well as the deacetylase activity of Sir2p. These data support a model for the spreading of silenced chromatin involving cycles of nucleosome deacetylation by Sir2p followed by recruitment of additional Sir2p, Sir3p, and Sir4p to the newly deacetylated nucleosome. This model suggests mechanisms for boundary formation, and for maintenance and inheritance of silenced chromatin. The principles are generalizable to other types of heritable chromatin states.

Animals↗
PubMed2004

Vascular endothelial-cadherin regulates cytoskeletal tension, cell spreading, and focal adhesions by stimulating RhoA.

Changes in vascular endothelial (VE)-cadherin-mediated cell-cell adhesion and integrin-mediated cell-matrix adhesion coordinate to affect the physical and mechanical rearrangements of the endothelium, although the mechanisms for such cross talk remain undefined. Herein, we describe the regulation of focal adhesion formation and cytoskeletal tension by intercellular VE-cadherin engagement, and the molecular mechanism by which this occurs. Increasing the density of endothelial cells to increase cell-cell contact decreased focal adhesions by decreasing cell spreading. This contact inhibition of cell spreading was blocked by disrupting VE-cadherin engagement with an adenovirus encoding dominant negative VE-cadherin. When changes in cell spreading were prevented by culturing cells on a micropatterned substrate, VE-cadherin-mediated cell-cell contact paradoxically increased focal adhesion formation. We show that VE-cadherin engagement mediates each of these effects by inducing both a transient and sustained activation of RhoA. Both the increase and decrease in cell-matrix adhesion were blocked by disrupting intracellular tension and signaling through the Rho-ROCK pathway. In all, these findings demonstrate that VE-cadherin signals through RhoA and the actin cytoskeleton to cross talk with cell-matrix adhesion and thereby define a novel pathway by which cell-cell contact alters the global mechanical and functional state of cells.

Animals↗
PubMed2004

The phosphorylation of vinculin on tyrosine residues 100 and 1065, mediated by SRC kinases, affects cell spreading.

Vinculin is a conserved actin binding protein localized in focal adhesions and cell-cell junctions. Here, we report that vinculin is tyrosine phosphorylated in platelets spread on fibrinogen and that the phosphorylation is Src kinases dependent. The phosphorylation of vinculin on tyrosine was reconstituted in vanadate treated COS-7 cells coexpressing c-Src. The tyrosine phosphorylation sites in vinculin were mapped to residues 100 and 1065. A phosphorylation-specific antibody directed against tyrosine residue 1065 reacted with phosphorylated platelet vinculin but failed to react with vinculin from unstimulated platelet lysates. Tyrosine residue 1065 located in the vinculin tail domain was phosphorylated by c-Src in vitro. When phosphorylated, the vinculin tail exhibited significantly less binding to the vinculin head domain than the unphosphorylated tail. In contrast, the phosphorylation did not affect the binding of vinculin to actin in vitro. A double vinculin mutant protein Y100F/Y1065F localized to focal adhesion plaques. Wild-type vinculin and single tyrosine phosphorylation mutant proteins Y100F and Y1065F were significantly more effective at rescuing the spreading defect of vinculin null cells than the double mutant Y100F/Y1065F. The phosphorylation of vinculin by Src kinases may be one mechanism by which these kinases regulate actin filament assembly and cell spreading.

Animals↗
PubMed2005

Src and FAK kinases cooperate to phosphorylate paxillin kinase linker, stimulate its focal adhesion localization, and regulate cell spreading and protrusiveness.

The ArfGAP paxillin kinase linker (PKL)/G protein-coupled receptor kinase-interacting protein (GIT)2 has been implicated in regulating cell spreading and motility through its transient recruitment of the p21-activated kinase (PAK) to focal adhesions. The Nck-PAK-PIX-PKL protein complex is recruited to focal adhesions by paxillin upon integrin engagement and Rac activation. In this report, we identify tyrosine-phosphorylated PKL as a protein that associates with the SH3-SH2 adaptor Nck, in a Src-dependent manner, after cell adhesion to fibronectin. Both cell adhesion and Rac activation stimulated PKL tyrosine phosphorylation. PKL is phosphorylated on tyrosine residues 286/392/592 by Src and/or FAK and these sites are required for PKL localization to focal adhesions and for paxillin binding. The absence of either FAK or Src-family kinases prevents PKL phosphorylation and suppresses localization of PKL but not GIT1 to focal adhesions after Rac activation. Expression of an activated FAK mutant in the absence of Src-family kinases partially restores PKL localization, suggesting that Src activation of FAK is required for PKL phosphorylation and localization. Overexpression of the nonphosphorylated GFP-PKL Triple YF mutant stimulates cell spreading and protrusiveness, similar to overexpression of a paxillin mutant that does not bind PKL, suggesting that failure to recruit PKL to focal adhesions interferes with normal cell spreading and motility.

Adaptor Proteins, Signal Transducing↗
PubMed2006

Bypassing the catalytic activity of SIR2 for SIR protein spreading in Saccharomyces cerevisiae.

Sir protein spreading along chromosomes and silencing in Saccharomyces cerevisiae requires the NAD+-dependent histone deacetylase activity of Sir2p. We tested whether this requirement could be bypassed at the HM loci and telomeres in cells containing a stably expressed, but catalytically inactive mutant of Sir2p, sir2-345p, plus histone mutants that mimic the hypoacetylated state normally created by Sir2p. Sir protein spreading was rescued in sir2-345 mutants expressing histones in which key lysine residues in their N-termini had been mutated to arginine. Mating in these mutants was also partially restored upon overexpression of Sir3p. Together, these results indicate that histone hypoacetylation is sufficient for Sir protein spreading in the absence of production of 2'-O-acetyl-ADP ribose by sir2p and Sir2p's enzymatic function for silencing can be bypassed in a subset of cells in a given population. These results also provide genetic evidence for the existence of additional critical substrates of Sir2p for silencing in vivo.

Catalysis↗
PubMed1977

Spread of extradural analgesia following caudal injection in children. A statistical study.

Data on the segmental spread of analgesia from three independent studies of caudal extradural blocks in children with three different local anaesthetic agents were examined with multiple regression techniques to find the effects of age on dose requirements. All three studies confirmed the existence of a linear relationship between the spread of analgesia and age. As there were no significant differences between the three regression lines a common regression line was calculated. This may be used as a guideline for predicting dose requirements in the daily routine of anaesthesia. By injecting a mixture of a radio-opaque substance and 4% lignocaine it was shown by comparison of the radiological spread of the solution and the distribution of clinical analgesia that the latter always exceeded the former by four to six segments. This may indicate the occurrence of diffusion.

Age Factors↗
PubMed1982

Effects of posture on the spread of spinal anaesthesia with isobaric 0.75% or 0.5% bupivacaine.

In a double-blind study the effects of posture on the spread of 3 ml of isobaric bupivacaine 5 and 7.5 mg ml-1 were compared after intrathecal injection in 40 patients undergoing orthopaedic surgery. Three millilitre of isobaric bupivacaine 7.5 mg mg-1 administered with the patient in a sitting position during and for 2.5 min after injection produced the highest spread of analgesia (T4). Horizontal posture, and the smaller dose in both positions, resulted in spread of analgesia to T7-8. Motor block in the legs was good in all cases. Horizontal posture at the time of injection resulted in the longest mean duration of analgesia and motor block, although there was no statistically significant difference in mean times between the groups. The longest mean duration of pin-prick analgesia (329 +/- 23 min) was in the patients injected in the horizontal posture with bupivacaine 7.5 mg ml-1. The course of anaesthesia and recovery were uneventful in all patients.

Aged↗
PubMed1989

Spread of spinal anaesthesia with plain 0.5% bupivacaine: influence of the vertebral interspace used for injection.

Three millilitre of plain 0.5% bupivacaine was injected intrathecally at two different levels in two groups of 20 patients. Injection at the L2/3 space produced a significantly higher spread of analgesia (mean T7 (SD 3.9)) than injection at L4/5 (T11(1.8)). The range of the cephalad spread of the block was less in the L4/5 group (P less than 0.001 at 60 min). The spread of anaesthesia continued beyond 30 min in both groups. In all patients anaesthesia sufficient for surgery of the knee and the foot was achieved. One patient had a final block level of T1 after injection at L2/3, accompanied by transient arterial hypotension.

Adult↗
PubMed1990

Influence of obesity on the spread of spinal analgesia after injection of plain 0.5% bupivacaine at the L3-4 or L4-5 interspace.

Spinal anaesthesia was compared in 40 obese patients (increased body mass index (BMI] and 40 patients with normal BMI when 3 ml of plain 0.5% bupivacaine was injected at either the L3-4 or L4-5 interspace. More extensive cephalad spread of sensory block was achieved in patients with increased BMI compared with patients with normal BMI after injection at both L3-4 and L4-5 (P less than 0.05). The use of the L3-4 interspace instead of L4-5 resulted in a higher mean spread of block in patients with both increased (T4 vs T8) or normal (T9 vs T11) BMI (P less than 0.05). The interindividual variability of the blocks was relatively small in patients with normal BMI injected at L4-5, compared with the three other groups (normal BMI injected at L3-4, increased BMI injected at L3-4 and L4-5). Good anaesthesia was produced in all patients for orthopaedic surgery of the lower extremity. In an obese patient it is recommended that plain bupivacaine be administered at L4-5 instead of L3-4 when extensive spread of the block is to be avoided.

Adult↗
PubMed1992

Prediction of the spread of repeated spinal anaesthesia with bupivacaine.

We have studied in 56 patients the predictability of spread of repeated spinal anaesthesia in the same patient on the basis of a previous block. With plain 0.5% bupivacaine, prediction of the second block was accurate. A significantly higher or lower spread of analgesia than in the previous block was achieved when plain 0.5% bupivacaine was administered using a modified technique--sitting position or lower interspace, respectively. When hyperbaric 0.5% bupivacaine was injected instead of plain solution for the second block using a similar technique, no baricity-related correlation was found between the first and second blocks. Change in technique did not reduce interindividual variation in the spread of analgesia. We conclude that individual anatomical properties may play a more important role than, for example, baricity in subarachnoid distribution of a local anaesthetic solution.

Adolescent↗
PubMed1993

Spread of spinal anaesthesia for caesarean section in singleton and twin pregnancies.

We have compared the spread of spinal anaesthesia in parturients with singleton and those with twin pregnancies. Fifty-five unpremedicated patients with uncomplicated pregnancy scheduled for Caesarean section were allocated to two groups: group I = 35 singleton mothers; group II = 20 with twin pregnancy. Both groups received spinal anaesthesia with hyperbaric bupivacaine 10 mg (2 ml of 0.5%). Mean birthweight was 3290 (SD 452) g and 5008 (495) g in groups I and II (combined birthweights), respectively. We found a statistically significant difference in onset and maximal cephalad spread of spinal anaesthesia (group I median T5, range T8-T4; group II T3, range T6-T2). The mechanisms of higher cephalad spread of spinal anaesthesia in parturients may be a decrease in cerebrospinal fluid volume secondary to shunting of blood from the obstructed inferior vena cava to the extradural venous plexus and increased nerve sensitivity to local anaesthetics because of increased concentrations of progesterone. The twin pregnancy group had heavier, larger uteri and greater daily production of progesterone.

Adult↗
PubMed1995

Extensive extradural spread in the elderly may not relate to decreased leakage through intervertebral foramina.

It has been suggested that the extensive longitudinal extradural spread of local anaesthetics in the elderly is attributed to decreased leakage through the intervertebral foramina. We have examined radiologically, in 53 patients, the relationship between leakage of iohexol through the thoracic intervertebral foramina and age. Iohexol was injected through an extradural catheter advanced 5 cm cephalad from one of the interspaces between T6 and T12. A significant correlation was observed between longitudinal spread of iohexol and age, but there was no correlation between leakage of iohexol through the intervertebral foramina and age. Our data suggest that longitudinal extradural spread of local anaesthetics in the elderly may not be attributed to decreased leakage through the intervertebral foramina.

Adult↗
PubMed1998

A beta 1 integrin signaling pathway involving Src-family kinases, Cbl and PI-3 kinase is required for macrophage spreading and migration.

We have used mutant macrophages which are deficient in expression of Src-family kinases to define an integrin signaling pathway that is required for macrophage adhesion and migration. Following ligation of surface integrins by fibronectin, the p120(c-cbl) (Cbl) protein rapidly becomes tyrosine phosphorylated and associated with the Src-family kinases Fgr and Lyn. In hck-/-fgr-/-lyn-/- triple mutant cells, which are defective in spreading on fibronectin-coated surfaces in vitro and show impaired migration in vivo, Cbl tyrosine phosphorylation is blocked, Cbl protein levels are low, adhesion-dependent translocation of Cbl to the membrane is impaired and Cbl-associated, membrane-localized phosphatidylinositol 3 (PI-3)-kinase activity is dramatically reduced. In contrast, adhesion-dependent activation of total cellular PI-3 kinase activity is normal in mutant cells, demonstrating that it is the membrane-associated fraction of PI-3 kinase which is most critical in regulating actin cytoskeletal rearrangements that lead to cell spreading. Treatment of wild-type cells with the Src-family-specific inhibitor PP1, Cbl antisense oligonucleotides or pharmacological inhibitors of PI-3 kinase blocks cell spreading on fibronectin surfaces. These data provide a molecular description for the role of Src-family kinases Hck, Fgr and Lyn in beta 1-integrin signal transduction in macrophages.

Animals↗