title stringlengths 0 1.13k | abstract stringlengths 1 15.7k | PMID int64 22 36.5M |
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Differential distribution of synGAP alpha1 and synGAP beta isoforms in rat neurons. | The synaptic Ras-GTPase activating protein synGAP is a brain-specific protein of approximately 130 kDa and is a negative regulator of Ras. We previously reported 5 C-terminal isoforms of synGAP (alpha1, alpha2, beta1/2, beta 3/4 and gamma) [Li et al., 2001, J. Biol. Chem. 276: 21417-21424]. In this study, we investigated the expression profiles of the two major isoforms, synGAP alpha1 and synGAP beta, in the adult rat brain and cultured neurons of the rat hippocampus. Examination of pepsin-pretreated brain sections demonstrated that both isoforms were expressed mainly in the forebrain structures, which suggests their association with postsynaptic density. The distribution of the synGAP alpha1 and beta (beta1-4) isoforms in the adult rat brain was clearly different in cerebellum, hippocampus, cerebral cortex, septum and olfactory bulb. In particular, synGAP alpha1 was specifically localized to the cerebellar glomeruli, dense synaptic sites. From the analysis using cultured neurons, unique expression of synGAP beta was found in a neuron with a sea urchin-like morphology, possibly a star pyramidal neuron, in which the synGAP beta expression was relatively high, in particular, at the distal part of its processes. SynGAP alpha1 was mostly or specifically localized to excitatory postsynaptic sites, whereas synGAP beta was present at both excitatory and inhibitory postsynaptic sites. Finally, there are more non-synaptic clusters in dendrites in the case of synGAP beta than synGAP alpha1. Thus, the two synGAP isoforms, alpha1 and beta, distribute differently in neuronal cells and the brain. | 18,824,155 |
High glucose increases RAW 264.7 macrophages activation by lipoteichoic acid from Staphylococcus aureus. | Type 2 diabetes mellitus is associated with an increased risk of cardiovascular diseases and accelerated atherosclerosis, which has been associated to hyperglycemia and chronic inflammation. Activated macrophages are described to participate in atherosclerosis due to foam cell formation and pro-inflammatory mediators production. Bacterial infections are described to accelerate atherosclerosis, moreover, gram-positive and negative bacterial DNA was described in atherosclerotic plaques. We studied the glucose modulation of RAW 264.7 macrophages activation by the gram-positive bacterial antigen lipoteichoic acid (LTA), evaluating nitrite production, tumor necrosis factor alpha secretion and matrix metalloproteinase 9 activity. High glucose increased macrophages activation by LTA, evidenced by exacerbated nitric oxide and tumor necrosis factor alpha production, as well matrix metalloproteinase 9 secretion. These effects could contribute to atherosclerotic risk parameters, like atherome plaque instability, and participate in chronic inflammation present in type 2 diabetes. | 18,824,162 |
Long-term cyclic stretch controls pulmonary endothelial permeability at translational and post-translational levels. | We have previously described differential effects of physiologic (5%) and pathologic (18%) cyclic stretch (CS) on agonist-induced pulmonary endothelial permeability. This study examined acute and chronic effects of CS on agonist-induced intracellular signaling and cell morphology in the human lung macro- and microvascular endothelial cell (EC) monolayers. Endothelial permeability was assessed by analysis of morphological changes, parameters of cell contraction and measurements of transendothelial electrical resistance. Exposure of both microvascular and macrovascular EC to 18% CS for 2-96 h increased thrombin-induced permeability and monolayer disruption. Interestingly, the ability to promote thrombin responses was present in EC cultures exposed to 48-96 h of CS even after replating onto non-elastic substrates. In turn, physiologic CS preconditioning (72 h) attenuated thrombin-induced paracellular gap formation and MLC phosphorylation in replated EC cultures. Long-term preconditioning at 18% CS (72 h) increased the content of signaling and contractile proteins including Rho GTPase, MLC, MLC kinase, ZIP kinase, PAR1, caldesmon and HSP27 in the pulmonary microvascular and macrovascular cells. We conclude that short term CS regulates EC permeability via modulation of agonist-induced signaling, whereas long-term CS controls endothelial barrier at both post-translational level and via magnitude-dependent regulation of pulmonary EC phenotype, signaling and contractile protein expression. | 18,824,167 |
Serial culture of murine primary airway epithelial cells and ex vivo replication of human rhinoviruses. | Human rhinoviruses (HRV) are the primary etiological agents in cold infections, and represent a serious risk to individuals with chronic respiratory disease such as asthma. In order to develop treatment options for HRV infections, murine models are a crucial component in the study of infection mechanisms due to the wide array of reagents and techniques available to study murine immunology. We present here a cell culture system for studying isolated murine epithelial cell responses to HRV. Monolayers of primary mouse airway epithelial cells were maintained in a serial culture system, and the identity and purity of the cell population was confirmed via immunostaining (positive for cytokeratin, negative for vimentin). Infection of these cells with a minor group rhinovirus (HRV-1A) was evidenced by increases in viral RNA, de novo synthesis of viral proteins, and production of infectious virus. This model will be useful in experiments to define mechanisms of viral replication and host/virus interactions within airway epithelial cells. | 18,824,171 |
Neurophysiological indices of perceptual object priming in the absence of explicit recognition memory. | The aim of this study was to identify ERP correlates of perceptual object priming that are insensitive to factors affecting explicit, episodic memory. EEG was recorded from 21 participants while they performed a visual object recognition test on a combination of unstudied items and old items that were previously encountered during either a 'deep' or 'shallow' levels-of-processing (LOP) study task. The results demonstrated a midline P150 old/new effect which was sensitive only to objects' old/new status and not to the accuracy of recognition responses to old items, or to the LOP manipulation. Similar outcomes were observed for the subsequent P200 and N400 effects, the former of which had a parietal scalp maximum and the latter, a broadly distributed topography. In addition an LPC old/new effect typical of those reported in past ERP recognition studies was observed. These outcomes support the proposal that the P150 effect is reflective of perceptual object priming and moreover, provide novel evidence that this and the P200 effect are independent of explicit recognition memory process(es). | 18,824,201 |
Frontal-midline theta from the perspective of hippocampal "theta". | Electrical recordings from the surface of the skull have a wide range of rhythmic components. A major task of analysis of this EEG is to determine their source and functional significance. The hippocampal "theta rhythm" has been extensively studied in rats and its rhythmicity has recently been shown to be functionally significant, per se. Here, we use relevant aspects of the hippocampal literature to provide perspective on one of the most studied human EEG rhythms: frontal-midline theta. We review its electrographic features, localization, prevalence, age distribution, behavioural modulation (particularly in relation to working memory, spatial navigation, episodic memory, internalised attention and meditation), relationship to personality, drug interactions, neurochemical relationships, and coherence with rhythmic activity at other sites. We conclude that FM-theta, like hippocampal theta, appears to play a role in (or at least occur during) processing of memory and emotion. It is correlated with working memory and/or sustained attention; but this does not entail a role in function since clear behavioural correlates of hippocampal theta have been demonstrated that are not sensitive to hippocampal damage. FM-theta is increased by anxiolytic drug action and personality-related reductions in anxiety, whereas hippocampal theta is decreased by anxiolytic drugs. In animals, frontal theta and hippocampal theta can be phase-locked or independent, depending on behavioural state. So, the cognitive functions of FM-theta, and their relationship to hippocampal theta, are unclear and definitive evidence for functional involvement in cognitive or emotional processing is lacking. One possible solution to this problem is analysis of FM-theta in animals-provided homology can be determined. The issues of sporadicity and low incidence of FM-theta also need to be addressed in the future. Changes in functional connectivity, indicated by changes in coherence, are also a largely untapped resource. We suggest that the most hopeful path to assessing the functions of FM-theta will be through the use of drugs, and the variation of their effects depending on baseline levels of FM-theta. Finally, we review some theories of theta function. Despite the apparent richness of the current data, we conclude that it is difficult (and may ultimately be impossible) to formulate a theory that attributes a specific cognitive function to FM-theta. However, the theories share some general computational assumptions and these should be a useful guide to future work and, ultimately, a definite theory of the function or functions of FM-theta. | 18,824,212 |
Intranasal administration of progesterone increases dopaminergic activity in amygdala and neostriatum of male rats. | We evaluated the effects of intranasal administration of progesterone (PROG) on the activity of dopaminergic neurons in the brain of anesthetized rats by means of microdialysis. Male Wistar rats were implanted with guide cannulae in the basolateral amygdala and neostriatum. Three to 5 days later, they were anesthetized with urethane, and dialysis probes were inserted. After a stabilization period of 2 h, four 30-min samples were collected. Thereafter, the treatment (0.5, 1.0 or 2.0 mg/kg of PROG dissolved in a viscous castor oil mixture, or vehicle) was applied into the nose in a volume of 10 microl (5 microl in each nostril). In other animals, an s.c. injection of PROG (1.0, 2.0 or 4.0 mg/kg) or vehicle was given. Samples of both application ways were collected at 30-min interval for 4 h after the treatment and immediately analyzed with high performance liquid chromatography and electrochemical detection. Intranasal administration of 2 mg/kg of PROG led to an immediate (within 30 min after the treatment) significant increase in the basolateral amygdala dopamine levels. In the neostriatum, the 2 mg/kg dose led to a delayed significant increase in dopamine. S.c. administration of 4 mg/kg of PROG was followed by a delayed significant increase in dopamine, both, in the basolateral amygdala and neostriatum, but smaller in magnitude in comparison to the intranasal treatment. This is the first study to demonstrate dopamine-enhancing effects of PROG, not only in the neostriatum, but also in the basolateral amygdala. Our results indicate that the intranasal route of administration of PROG is a more efficacious way for targeting the brain than the s.c. route. | 18,824,215 |
The CYPome (Cytochrome P450 complement) of Aspergillus nidulans. | The cytochromes P450 (CYPs) are found in all biological kingdoms and genome sequencing projects continue to reveal an ever increasing number. The principle aim of this paper is to identify the complete CYPome of Aspergillus nidulans from the genome sequence version AN.3 deposited at the Broad institute, assign the appropriate CYP nomenclature and define function where possible. The completed analysis revealed a total of 111 CYP genes, 3 of which were previously unknown and 8 pseudogenes, representing 89CYP families, 21 of which are unique. We have identified 28 potential gene clusters associated with one or more CYP genes and discussed those with putative PKS and NRPS associated function. The chromosomal location of the genes, predicted cellular location of the proteins and possible function(s) are discussed. | 18,824,241 |
Physiological relevance of GPCR oligomerization and its impact on drug discovery. | The potentially large functional and physiological diversity of G-protein coupled receptor (GPCR) dimers has generated a great deal of excitement about the opportunity that dimerization provides for enabling novel drug discovery. The discovery of physiologically relevant GPCR dimers suggests that new drug targets for diseases such as schizophrenia and pre-eclampsia can be developed by targeting dimers. Most of the previous work on GPCR dimers made use of the overexpression of differentially tagged GPCRs in heterologous cell systems. Current emphasis on the development of physiologically relevant cell systems that endogenously express the appropriate combination of GPCR dimers and accessory proteins is leading to dramatic increases in our understanding of GPCR dimers. These and other new tools such as GPCR-specific antibodies will be required to develop GPCR dimer specific drugs. Given that ligands are available for only a small percentage of the large number of potentially druggable GPCRs, the use of GPCR dimers might provide the necessary targets to increase the breadth and depth of receptors available for therapeutic interventions. | 18,824,244 |
New therapeutics for the prevention and reduction of scarring. | Published literature shows that both physicians and patients are highly concerned about scarring and value even small improvements in scar appearance. Both severe and relatively minor scars can have a significant psychological impact on patients, irrespective of whether or not they are hidden by clothing. There is no universal standard of care for scarring and, currently, no marketed pharmaceuticals for the prophylactic reduction of scarring. Novel approaches are under development, with the furthest progressed being avotermin (Juvista; transforming growth factor beta 3). The scar-improvement efficacy of this agent, administered at the time of surgery, has been demonstrated in robust, well-controlled, randomized human studies. Avotermin and other agents in development represent a new class of prophylactic medicines promoting the regeneration of normal skin and improving scar appearance. | 18,824,245 |
Inhibitory effect of olive oil on fibrosis induced by carbon tetrachloride in rat liver. | In this study, the inhibitory effect of olive oil on liver fibrosis induced by carbon tetrachloride (CCl(4)) has been investigated in rats. Rats were divided randomly into four groups: control, CCl(4), and two olive oil groups. Except for rats in the control group, all rats were orally administered CCl(4) twice a week for 8 weeks. Rats in the olive oil groups were treated daily with olive oil (2 or 10 ml/kg) through gastrogavage for the entire experimental period. RT-PCR analysis showed that CCl(4) increased the hepatic mRNA expressions of lipopolysaccharide binding protein, CD14, Toll-like receptor-4, NADPH oxidase, nuclear factor-kappa beta, collagen (alpha1) (I), collagen (alpha1) (III), and transforming growth factor beta1. The expression of these mRNAs could be decreased by olive oil treatment. In addition, Western blot analysis also supported these results. CCl(4)-induced liver damage, as characterized by the increase in hepatic malondialdehyde and hydroxyproline levels. Olive oil treatment decreased the hepatic malondialdehyde and hydroxyproline levels. Histological evaluations showed that olive oil could attenuate the liver fibrosis, necrosis, and expression of smooth muscle alpha-actin that are induced by CCl(4). It is speculated that the phenolic compounds in olive oil significantly reduced CCl(4)-induced hepatic fibrosis in rats. | 18,824,281 |
C60 fullerene: a powerful antioxidant or a damaging agent? The importance of an in-depth material characterization prior to toxicity assays. | Since the discovery of fullerenes in 1985, these carbon nanospheres have attracted attention regarding their physico/chemical properties. Despite little knowledge about their impact on the environment and human health, the production of fullerenes has already reached an industrial scale. However, the toxicity of C(60) is still controversially discussed. The aim of this study was to clarify the biological effects of tetrahydrofuran (THF) suspended C(60) fullerene in comparison to water stirred C(60) fullerene suspensions. Beyond that, we analyzed the effects on the Crustacea Daphnia magna an indicator for ecotoxicological effects and the human lung epithelial cell line A549 as a simplified model for the respiratory tract. We could demonstrate that water-soluble side products which were formed in THF nC(60) suspension were responsible for the observed acute toxic effects, whereas fullerenes themselves had no negative effect regardless of the preparative route on either A549 cell in vitro or D. magna in vivo. | 18,824,284 |
Quantitative detection of survivin in malignant pleural effusion for the diagnosis and prognosis of lung cancer. | In the present study, pleural effusions are the first time to be used as the specimens for detection of survivin expression in lung cancer patients. We demonstrated that by quantifying survivin expression with enzyme-linked immunosorbent assay (ELISA) in the 80 effusion samples exhibited a diagnostic power of 85% and 75% in sensitivity and specificity, respectively. A multivariate analysis with the Cox regression model revealed that both high survivin expression and cancer cells of stage IV were the indicators for poor prognosis of lung cancer. In conclusion, quantitative assay of survivin in pleural effusion could be useful both in diagnosis and prognosis for lung cancer. | 18,824,294 |
Ametryn degradation in the ultraviolet (UV) irradiation/hydrogen peroxide (H2O2) treatment. | Ultraviolet (UV) irradiation (253.7nm) in the presence of hydrogen peroxide (H(2)O(2)) was used to decompose aqueous ametryn. The concentrations of ametryn were measured with time under various experiment conditions. The investigated factors included H(2)O(2) dosages, initial pH, initial ametryn concentrations, and a variety of inorganic anions. Results showed that ametryn degradation in UV/H(2)O(2) process was a pseudo-first-order reaction. Removal rates of ametryn were greatly affected by H(2)O(2) dosage and initial concentrations of ametryn, but appeared to be slightly influenced by initial pH. Furthermore, we investigated the effects of four anions (SO(4)(2-), Cl(-), HCO(3)(-), and CO(3)(2-)) on ametryn degradation by UV/H(2)O(2). The impact of SO(4)(2-) seemed to be insignificant; however, Cl(-), HCO(3)(-), and CO(3)(2-) considerably slowed down the degradation rate because they could strongly scavenge hydroxyl radicals (OH) produced during the UV/H(2)O(2) process. Finally, a preliminary cost analysis revealed that UV/H(2)O(2) process was more cost-effective than the UV alone in removal of ametryn from water. | 18,824,296 |
[Inhibition of bacterial adhesion and prevention of biofilm formation: Use of organic self-assembled monolayers on inorganic surfaces]. | Implant related nosocomial infections are a serious public health concern. Colonisation by contaminating bacteria of the bare implant surface may lead to the formation of a biofilm protecting bacteria against host defences and antibiotics. To decrease the risk of infection, a strategy is to modify the biomaterial surface by an antibacterial coating, inhibiting bacterial adhesion ("passive" coatings) or able to kill bacteria ("active" coatings). This article describes the potential of self-assembled monolayers as antibacterial coatings allowing the molecular level control of the surface properties of inorganic substrates. After a presentation of the compounds used to form self-assembled monolayers, we present the literature dealing with antibacterial monolayers and the latest developments concerning "active" phosphonate monolayers that significantly inhibit the growth of bacterial biofilm. | 18,824,310 |
Cloning and expression of an antifungal chitinase gene of a novel Bacillus subtilis isolate from Taiwan potato field. | A chitinase producing Bacillus subtilis CHU26 was isolated from Taiwan potato field. This strain exhibited a strong extra-cellular chitinase activity on the colloidal chitin containing agar plate, and showed a potential inhibit activity against phytopathogen, Rhizoctonia solani. The gene encoding chitinase (chi18) was cloned from the constructed B. subtilis CHU26 genomic DNA library. The chi18 consisted of an open reading frame of 1791 nucleotides and encodes 595 amino acids with a deduced molecular weight of 64kDa, next to a promoter region containing a 9 base pair direct repeat sequence (ATTGATGAA). The deduced amino acid sequence of the chitinase from Bacillus subtilis CHU26 exhibits 62% and 81% similarity to those from B. circulans WL-12 and B. licheniformis, respectively. Subcloned chi18 into vector pGEM3Z and pYEP352 to construct recombinant plasmid pGCHI18 and pYCHI18, respectively, chitinase activity could be observed on the colloidal chitin agar plate from recombinant plasmid containing Escherichia coli transformant. Cell-free culture broth of pYCHI18 containing E. coli transformant decreased R. solani pathogenic activity more than 90% in the antagonistic test on the radish seedlings (Raphanus sativus Linn.). | 18,824,348 |
Validation of two echocardiographic indexes to improve the diagnosis of complex coarctations. | Coarctation of the aorta is one of the most common congenital heart defects. Its diagnosis may be difficult in the presence of a patent ductus arteriosus, of other complex defects or of a poor echocardiographic window. We sought to demonstrate that the carotid-subclavian artery index (CSA index) and the isthmus-descending aorta ratio (I/D ratio), two recently described echocardiographic indexes, are effective in detection of isolated and complex aortic coarctations in children younger and older than 3 months of age. The CSA index is the ratio of the distal aortic arch diameter to the distance between the left carotid artery and the left subclavian artery. It is highly suggestive of a coarctation when it is <1.5. The I/D ratio defined as the diameter of the isthmus to the diameter of the descending aorta, suggests an aortic coarctation when it is less than 0.64. This is a retrospective cohort study in a tertiary care children's hospital. Review of all echocardiograms in children aged 0-18 years with a diagnosis of coarctation seen at the author's institution between 1996 and 2006. An age- and sex-matched control group without coarctation was constituted. Offline echocardiographic measurements of the aortic arch were performed in order to calculate the CSA index and I/D ratio. Sixty-eight patients were included in the coarctation group, 24 in the control group. Patients with coarctation had a significantly lower CSA index (0.84+/-0.39 vs 2.65+/-0.82, p<0.0001) and I/D ratio (0.58+/-0.18 vs 0.98+/-0.19, p<0.0001) than patients in the control group. Associated cardiac defects and age of the child did not significantly alter the CSA index or the I/D ratio. A CSA index less than 1.5 is highly suggestive of coarctation independent of age and of the presence of other cardiac defects. I/D ratio alone is less specific than CSA alone at any age and for any associated cardiac lesion. The association of both indexes improves sensitivity and permits diagnosis of coarctation in all patients based solely on a bedside echocardiographic measurement. | 18,824,366 |
[Median nerve entrapment after fracture dislocation of the elbow: a two-cases report]. | The median nerve entrapment after elbow-dislocation is rare. We report two cases of fracture dislocation elbow completed by entrapment of median nerve occurred after reduction in two children. For both cases, the diagnosis of entrapment was made some months later after injury. Median nerve graft was performed after nerve resection. The nerve recovery was satisfactory at the final follow-up. This nerve complication should be suspected systematically before and after reduction of all dislocation of the elbow in the children. The indication of nerve release or nerve graft depends on the entrapment and the delay of the palsy. | 18,824,386 |
Evaluation of stretching position by measurement of strain on the ilio-femoral ligaments: an in vitro simulation using trans-lumbar cadaver specimens. | The ilio-femoral ligament is known to cause flexion contracture of the hip joint. Stretching positioning is intended to elongate the ilio-femoral ligaments, however, no quantitative analysis to measure the effect of stretching positions on the ligament has yet been performed. Strains on the superior and inferior ilio-femoral ligaments in 8 fresh/frozen trans-lumbar cadaveric hip joints were measured using a displacement sensor, and the range of movement of the hip joints was recorded using a 3Space Magnetic Sensor. Reference length (L(0)) for each ligament was determined to measure strain on the ligaments. Hip positions at 10 degrees adduction with maximal external rotation, 20 degrees adduction with maximal external rotation, and maximal external rotation showed larger strain for the superior ilio-femoral ligament than the value obtained from L(0), and hip positions at 20 degrees external rotation with maximal extension and maximal extension had larger strain for the inferior ilio-femoral ligament than the value obtained from L(0) (p<0.05). Superior and inferior ilio-femoral ligaments exhibited positive strain values with specific stretching positions. Selective stretching for the ilio-femoral ligaments may contribute to achieve lengthening of the ligaments to treat flexion contracture of the hip joint. | 18,824,394 |
The relocation of starch metabolism to chloroplasts: when, why and how. | Plastid endosymbiosis was accompanied by the appearance of a novel type of semi-cristalline storage polysaccharide (starch). Interestingly, starch is found in the cytoplasm of Rhodophyceae and Glaucophyta but is localized to the chloroplast stroma of Chloroplastida. The pathway is presumed to have been cytosolic in the common ancestor of the three Archaeplastida lineages. The means by which in green plants and algae an entire suite of nuclear-encoded starch-metabolism genes could have had their protein products rewired simultaneously to plastids are unclear. This opinion article reviews the timing and the possible reasons underlying this rewiring and proposes a hypothesis that explains its mechanism. The consequences of this mechanism on the complexity of starch metabolism in Chloroplastida are discussed. | 18,824,400 |
Markers that define stemness in ESC are unable to identify the totipotent cells in human preimplantation embryos. | During human preimplantation development, early blastomeres are believed to be totipotent. It is likely, however, that blastomeres are allocated to a specific lineage prior to any morphological differentiation. NANOG, SOX2 and SALL4 are transcription factors that play a key role in controlling stemness in embryonic stem cells (ESC) and are therefore candidate markers for developmental triggers in early embryos. KRT18, a trophoblast-determining gene, may mark early differentiation. Examining the expression pattern of these genes may inform us about when and in which cells totipotency is lost during early human development. Thirtheen oocytes, 124 preimplantation embryos and 7 human embryonic stem cell (hESC) lines were examined for the presence of NANOG, SOX2, SALL4 or KRT18 proteins using immunostaining and confocal microscopy. All stemness markers were expressed in the hESC, but none of them was specific for totipotent cells during human preimplantation development, and none of them seemed to mark cells allocated to the inner cell mass (ICM) or trophectoderm. After lineage specification, only the nuclear expression of NANOG and SOX2 became restricted to the ICM, at least to some cells because only a subpopulation expressed NANOG. KRT18 expression was seen for the first time during compaction in some outer cells. KRT18 was not expressed in hESC. We conclude that the protein expression patterns of markers that define stemness in ESC do not identify the totipotent cells in human preimplantation embryos. Assessing the presence of KRT18 proteins implied that the outer cells of compacting embryos have probably lost their totipotent competence prior to any visible differentiation. | 18,824,471 |
A dose distribution overlay technique for image guidance during prostate radiotherapy. | Adaptive radiotherapy involves altering the treatment plan according to variations in patient anatomy and set-up. This relies upon an accurate representation of the changing dose distribution within the patient, requiring a full dose recalculation. This work proposes a novel workflow using the planned dose distribution to assess dose coverage in three-dimensional verification CT studies acquired at the time of treatment delivery, using an overlay technique, in lieu of a recalculated dose distribution. The concept has been validated in a pilot study of 10 patients, each with 7-10 on-treatment CT studies. Differences between the geometric shape of the treatment plans for the 95% isodose and the 95% isodose obtained when the planned geometry was recalculated from the verification CT dataset were quantified. Dosimetric coverage of the verification clinical target volume (vCTV) was assessed for both the proposed overlay technique and the recalculated "delivered" dose distribution, and the conclusions on adequacy were compared. Results were consistent with geometric uncertainties of the dose calculation matrix (5 x 5 x 5 mm), suggesting that differences in the geometric shape of the 95% isodose are not significant for normal variations in patients' anatomy. Decisions on adequacy of vCTV coverage were consistent in 80 out of 87 cases, with discrepancies limited to a maximum of three axial slices per study within the range 0.5-4.5 mm (mean, 1.6 mm). The proposed dosimetric overlay technique has been validated and found to be an acceptable method of image-guided radiotherapy of the prostate suitable for effective implementation in the treatment clinic. | 18,824,502 |
The IkappaBalpha/NF-kappaB complex has two hot spots, one at either end of the interface. | IkappaBalpha binds to and inhibits the transcriptional activity of NF-kappaB family members via its ankyrin repeat (AR) domain. The binding affinity of IkappaBalpha with NF-kappaB(p50/p65) heterodimers and NF-kappaB(p65/65) homodimers is in the picomolar range, and in the cell, this results in long half-lives of the complexes. Direct binding experiments have been performed using surface plasmon resonance (SPR) and isothermal titration calorimetry (ITC) on a series of truncations and mutations in order to understand what regions of the interface are most important for the tight binding affinity of this complex. We previously showed that interactions between residues 305 and 321 of NF-kappaB(p65) with the first AR of IkappaBalpha are critical for the binding energy. Interactions in this region are responsible for more than 7 kcal/mol of the binding energy. Here we show equally drastic consequences for the binding energy occur upon truncation of even a few residues at the C terminus of IkappaBalpha. Thus, the interface actually has two hot spots, one at either end of the elongated and large surface of interaction. These results suggest a "squeeze" mechanism that leads to the extremely high affinity of the IkappaBalpha*NF-kappaB complex through stabilization of the ankyrin repeat domain. | 18,824,506 |
Characterization of the termination-reinitiation strategy employed in the expression of influenza B virus BM2 protein. | Coupled expression of the M1 and BM2 open-reading frames (ORFs) of influenza B from the dicistronic segment 7 mRNA occurs by a process of termination-dependent reinitiation. The AUG start codon of the BM2 ORF overlaps the stop codon of the upstream M1 ORF in the pentanucleotide UAAUG, and BM2 synthesis is dependent upon translation of the M1 ORF and termination at the stop codon. Here, we have investigated the mRNA sequence requirements for BM2 expression. Termination-reinitiation is dependent upon 45 nucleotide (nt) of RNA immediately upstream of the UAAUG pentanucleotide, which includes an essential stretch complementary to 18S rRNA helix 26. Thus, similar to the caliciviruses, base-pairing between mRNA and rRNA is likely to play a role in tethering the 40S subunit to the mRNA following termination at the M1 stop codon. Consistent with this, repositioning of the M1 stop codon more than 24 nt downstream from the BM2 start codon inhibited BM2 expression. RNA structure probing revealed that the RNA upstream of the UAAUG overlap is not highly structured, but upon encountering the M1 stop codon by the ribosome, a stem-loop may form immediately 5' of the ribosome, with the 18S rRNA complementary region in the apical loop and in close proximity to helix 26. Mutational analysis reveals that the normal requirements for start site selection in BM2 expression are suspended, with little effect of initiation codon context and efficient use of noncanonical initiation codons. This suggests that the full complement of initiation factors is not required for the reinitiation process. | 18,824,510 |
Diurnal variation in phagocytic activity of splenic phagocytes in freshwater teleost Channa punctatus: melatonin and its signaling mechanism. | The aim of the present study was to understand the rhythmic changes in innate immune response in freshwater fish Channa punctatus. Furthermore, the putative role of melatonin as the zeitgeber was explored. The phagocytic activity of splenic phagocytes assessed at 6-h intervals showed higher phagocytic activity during light phase than dark phase. The increased phagocytic activity during light phase was diminished by melatonin administration at 09:00 h. Implication of melatonin in control of diurnal variation in phagocytic activity was substantiated by administering irreversible tryptophan hydroxylase inhibitor, para-chlorophenylalanine (pCPA) at 18:00 h. pCPA abrogated the decrease of phagocytosis observed during dark phase, and the same was restored after melatonin administration. The direct involvement of melatonin in modulation of phagocytosis was demonstrated following in vitro experiments. Melatonin suppressed the phagocytic activity in a concentration-dependent manner without affecting the viability of phagocytes. The existence of functional membrane-bound melatonin receptors on fish phagocytes was pharmacologically demonstrated. Luzindole, melatonin membrane receptor antagonist, completely blocked the inhibitory effect of melatonin on phagocytosis. Further receptor-coupled adenylate cyclase-protein kinase A (PKA) pathway was implicated in transducing the melatonin effect as both adenylate cyclase and PKA inhibitor completely nullified the melatonin-induced suppression. An increased intracellular cAMP level in response to melatonin ascertained the second messenger status of cAMP for downstream signaling. However, manipulation of phospholipase C/PKC failed to influence the effect of melatonin on phagocytic activity. These observations in C. punctatus evidenced the diurnal rhythmicity in phagocytic activity that is regulated by melatonin following membrane-bound receptor-coupled cAMP-PKA pathway. | 18,824,520 |
A null allele impairs function of CYP2C76 gene in cynomolgus monkeys: a possible genetic tool for generation of a better animal model in drug metabolism. | The monkey CYP2C76 gene does not correspond to any of the human CYP2C genes, and its enzyme is at least partly responsible for the species difference occasionally seen in drug metabolism between monkeys and humans. To establish a line and/or lines of monkeys that are expected to show metabolic patterns highly similar to humans, we set out to find monkeys that lacked CYP2C76 activity. By genetic screening of 73 monkeys and a database search of expressed sequence tags, we found a total of 10 nonsynonymous genetic variants in the coding region of CYP2C76, including a null genotype (c.449TG>A). Some of the variants were differently distributed between two animal groups originating from different geographical regions (Indochina and Indonesia). After screening 170 additional genomic samples, we identified a total of eight animals (six males and two females) that were heterozygous for c.449TG>A, which could be used for establishing a homozygous line. If the homozygotes show drug-metabolizing properties more similar to humans than wild-type monkeys, the homozygotes may serve as a better animal model for drug metabolism. The data presented in this article provide the essential genetic information to perform a successful study by using cynomolgus monkeys and present a possible tool to generate a better animal model for drug metabolism. | 18,824,522 |
High-affinity interaction of sartans with H+/peptide transporters. | Sartans are very effective drugs for treatment of hypertension, heart failure, and other cardiovascular disorders. They antagonize the effects of angiotensin II at the AT(1) receptor and display p.o. bioavailability rates of 13 to 80%. Because some sartans sterically resemble dipeptide derivatives, we investigated whether they are transported by peptide transporters. We first assessed the effects of sartans on [(14)C]glycylsarcosine uptake into Caco-2 cells expressing H(+)/peptide transporter (PEPT) 1 and into SKPT cells expressing PEPT2. Losartan, irbesartan, valsartan, and eprosartan inhibited [glycine-1-(14)C]glycylsarcosine ([(14)C]Gly-Sar) uptake into Caco-2 cells in a competitive manner with K(i) values of 24, 230, 390, and >1000 microM. Losartan and valsartan also strongly inhibited the total transepithelial flux of [(14)C]Gly-Sar across Caco-2 cell monolayers. In SKPT cells, [(14)C]Gly-Sar uptake was inhibited with K(i) values of 2.2 microM (losartan), 65 microM (irbesartan), 260 microM (valsartan), and 490 microM (eprosartan). We determined by the two-electrode voltage-clamp technique whether the compounds elicited transport currents by PEPT1 or PEPT2 when expressed in Xenopus laevis oocytes. No currents were observed for any of the sartans, but the compounds strongly and reversibly inhibited peptide-induced currents. Uptake of valsartan, losartan, and cefadroxil was quantified in HeLa cells after heterologous expression of human PEPT1 (hPEPT1). In contrast to cefadroxil, no PEPT1-specific uptake of valsartan and losartan was found. We conclude that the sartans tested in this study display high-affinity interaction with PEPTs but are not transported themselves. However, they strongly inhibit hPEPT1-mediated uptake of dipeptides and cefadroxil. | 18,824,524 |
Adenoviral delivery of interleukin-10 fails to attenuate experimental Lyme disease. | Production of interleukin-10 (IL-10) by C57BL/6 mice following infection with Borrelia burgdorferi has been proposed as a mechanism whereby resistance to the development of experimental Lyme arthritis is maintained. In the current study, we sought to determine the role of IL-10 during infection of arthritis- and carditis-susceptible C3H mice. Infection of C3H IL-10(-/-) mice led to increased joint swelling and arthritis severity scores over those of wild-type C3H mice. Measurement of B. burgdorferi numbers in joints or disseminated tissues indicated a more efficient clearance of spirochetes in the absence of IL-10, similar to that reported in C57BL/6 IL-10(-/-) mice. However, in contrast to previous in vitro work, infection of C3H IL-10(-/-) mice led to decreased in vivo expression of the cytokines KC, IL-1beta, IL-4, and IL-12p70 in the infected joints. Finally, adenoviral expression of IL-10 in the infected joints of C3H mice was unable to modulate the development of severe Lyme arthritis and had no effect on spirochete clearance or Borrelia-specific antibody production. Development of Lyme carditis appeared to be independent of modulation by IL-10. These results suggest that IL-10 limits the development of joint inflammation in both arthritis-resistant and -susceptible mouse strains infected with B. burgdorferi and that increased IL-10 production cannot rescue genetic susceptibility to development of pathology in this model. | 18,824,530 |
Mycobacterium avium glycopeptidolipids require specific acetylation and methylation patterns for signaling through toll-like receptor 2. | Toll-like receptors (TLRs) recognize pathogen-associated molecules and play a vital role in promoting an immune response against invading microbes. TLR2, one of the key members of the TLR family, recognizes a wide variety of microbial products, including lipoproteins and lipopeptides, from a number of pathogens. Recent studies from our laboratory indicate that glycopeptidolipids (GPLs), a major surface component of Mycobacterium avium and other non-tuberculosis mycobacteria, are ligands for TLR2. However, the molecular requirements necessary for the GPL-TLR2 interaction were not defined in this report. In the present study we isolated different GPL species from M. avium, and using mass spectrometry and NMR analyses, characterized the molecular requirements of the GPL-TLR2 interaction. Interestingly, the extent of the respective acetylation and methylation of the 6-deoxytalose and rhamnose contained within the core GPL structure dictated whether the GPL signaled through TLR2. These experiments illustrate how subtle changes in a complex TLR2 ligand can alter its affinity for this important receptor, and suggest that M. avium could potentially modify its GPL structure to limit its interaction with TLR2. | 18,824,550 |
Costs and cost-effectiveness of different follow-up schedules for detection of occupational hepatitis C virus infection. | The purpose of this study was to compare the costs and cost-effectiveness (C/E) of early hepatitis C virus (HCV) RNA testing (alternative-US recommendations) after occupational exposure to HCV with existing follow-up strategies: (1) French, anti-HCV antibodies and alanine transaminase (ALT) activity at months 1, 3 and 6; (2) European, monthly ALT activity for 4 months and anti-HCV antibodies at month 6; (3) and baseline-US, anti-HCV antibodies and ALT activity at month 6. A decision tree simulated each strategy for 7300 healthcare workers (HCWs) exposed to HCV each year in France, taking into account the impact of early diagnosis on the response to antiviral treatment and the deterioration of HCW quality of life after exposure. For a HCV transmission risk of 0.5% after exposure, the French strategy led to the highest costs/person (181.40 euros) and the baseline-US strategy to the lowest (126.60 euros) (178.50 euros) for alternative-US). The shortest mean time to HCV infection diagnosis (1 month) and the lowest number of chronic hepatitis C (CHC) patients (1.9/7300 HCWs exposed) was obtained with the alternative-US strategy (vs 6 months and 7.9 CHC, respectively with baseline-US). Compared with the alternative-US, the French strategy was associated with higher costs and lower utilities, and the European with a higher incremental C/E ratio. Compared with the baseline-US strategy, the alternative-US strategy C/E ratio was 2020 euros per quality-adjusted life year saved. In HCWs exposed to HCV, a strategy based on early HCV RNA testing shortens the period during which the HCW's wait for his HCV status, leads to lower risk of progression to CHC and is reasonably cost-effective. | 18,824,553 |
Prospective evaluation of mitotane toxicity in adrenocortical cancer patients treated adjuvantly. | Toxicity of adjuvant mitotane treatment is poorly known; thus, our aim was to assess prospectively the unwanted effects of adjuvant mitotane treatment and correlate the findings with mitotane concentrations. Seventeen consecutive patients who were treated with mitotane after radical resection of adrenocortical cancer (ACC) from 1999 to 2005 underwent physical examination, routine laboratory evaluation, monitoring of mitotane concentrations, and a hormonal work-up at baseline and every 3 months till ACC relapse or study end (December 2007). Mitotane toxicity was graded using NCI CTCAE criteria. All biochemical measurements were performed at our center and plasma mitotane was measured by an in-house HPLC assay. All the patients reached mitotane concentrations >14 mg/l and none of them discontinued definitively mitotane for toxicity; 14 patients maintained consistently elevated mitotane concentrations despite tapering of the drug. Side effects occurred in all patients but were manageable with palliative treatment and adjustment of hormone replacement therapy. Mitotane affected adrenal steroidogenesis with a more remarkable inhibition of cortisol and DHEAS than aldosterone. Mitotane induced either perturbation of thyroid function mimicking central hypothyroidism or, in male patients, inhibition of testosterone secretion. The discrepancy between salivary and serum cortisol, as well as between total and free testosterone, is due to the mitotane-induced increase in hormone-binding proteins which complicates interpretation of hormone measurements. A low-dose monitored regimen of mitotane is tolerable and able to maintain elevated drug concentrations in the long term. Mitotane exerts a complex effect on the endocrine system that may require multiple hormone replacement therapy. | 18,824,557 |
Metastases but not cardiovascular mortality reduces life expectancy following surgical resection of apparently benign pheochromocytoma. | The treatment of choice for non-metastatic pheochromocytoma is surgical resection. Its goals are to abolish catecholamine hypersecretion, normalize blood pressure, and prevent further tumor growth or progression to metastatic disease. Data on long-term mortality and morbidity after pheochromocytoma surgery are limited. We here report a retrospective study on the long-term outcome after surgery for apparently benign pheochromocytoma at the Radboud University Nijmegen Medical Centre. Data on clinical presentation, treatment, post-surgical blood pressure and recurrence, metastasis and death were collected of 69 consecutive patients (January 1966-December 2000; follow-up: until death or January 2006). Survival was compared with survival of a matched reference population. Two patients died of surgical complications. All ten patients with metastatic disease (including three diagnosed at first surgery) died. At follow-up, 40 patients were alive and recurrence free and three patients were lost to follow up. Two patients experienced a benign recurrence. Mean+/-s.d. follow-up was 10.2+/-7.5 (median 9, range 1-38) years. Kaplan-Meier estimates for 5- and 10-year survival since surgery were 85.8% (95% CI: 77.2-94.4%) and 74.2% (95% CI: 62.0-86.4%) for patients versus 95.5 and 89.4% in the reference population (P<0.05). Sixty-four percent of all patients with hypertension prior to surgery showed a significant decrease in blood pressure, but remained hypertensive after surgery. In conclusion, compared with the general population patients have a reduced life expectancy following pheochromocytoma surgery, due to their risk of developing metastatic disease. Only one-third becomes normotensive without antihypertensive medication. Therefore, lifelong follow-up is warranted. | 18,824,558 |
Glycobiology on the fly: developmental and mechanistic insights from Drosophila. | Drosophila melanogaster offers many unique advantages for deciphering the complexities of glycan biosynthesis and function. The completion of the Drosophila genome sequencing project as well as the comprehensive catalogue of existing mutations and phenotypes have lead to a prolific database where many of the genes involved in glycan synthesis, assembly, modification, and recognition have been identified and characterized. Recent biochemical and molecular studies have elucidated the structure of the glycans present in Drosophila. Powerful genetic approaches have uncovered a number of critical biological roles for glycans during development that impact on our understanding of their function during mammalian development. Here, we summarize key recent findings and provide evidence for the usefulness of this model organism in unraveling the complexities of glycobiology across many species. | 18,824,561 |
The spindle assembly checkpoint is satisfied in the absence of interkinetochore tension during mitosis with unreplicated genomes. | The accuracy of chromosome segregation is enhanced by the spindle assembly checkpoint (SAC). The SAC is thought to monitor two distinct events: attachment of kinetochores to microtubules and the stretch of the centromere between the sister kinetochores that arises only when the chromosome becomes properly bioriented. We examined human cells undergoing mitosis with unreplicated genomes (MUG). Kinetochores in these cells are not paired, which implies that the centromere cannot be stretched; however, cells progress through mitosis. A SAC is present during MUG as cells arrest in response to nocodazole, taxol, or monastrol treatments. Mad2 is recruited to unattached MUG kinetochores and released upon their attachment. In contrast, BubR1 remains on attached kinetochores and exhibits a level of phosphorylation consistent with the inability of MUG spindles to establish normal levels of centromere tension. Thus, kinetochore attachment to microtubules is sufficient to satisfy the SAC even in the absence of interkinetochore tension. | 18,824,563 |
Notch1 signaling stimulates proliferation of immature cardiomyocytes. | The identification of the molecular mechanisms controlling cardiomyocyte proliferation during the embryonic, fetal, and early neonatal life appears of paramount interest in regard to exploiting this information to promote cardiac regeneration. Here, we show that the proliferative potential of neonatal rat cardiomyocytes is powerfully stimulated by the sustained activation of the Notch pathway. We found that Notch1 is expressed in proliferating ventricular immature cardiac myocytes (ICMs) both in vitro and in vivo, and that the number of Notch1-positive cells in the heart declines with age. Notch1 expression in ICMs paralleled the expression of its Jagged1 ligand on non-myocyte supporting cells. The inhibition of Notch signaling in ICMs blocked their proliferation and induced apoptosis; in contrast, its activation by Jagged1 or by the constitutive expression of its activated form using an adeno-associated virus markedly stimulated proliferative signaling and promoted ICM expansion. Maintenance or reactivation of Notch signaling in cardiac myocytes might represent an interesting target for innovative regenerative therapy. | 18,824,567 |
Human PMS2 deficiency is associated with impaired immunoglobulin class switch recombination. | Immunoglobulin (Ig) class switch recombination (CSR) deficiencies are rare primary immunodeficiencies characterized by the lack of switched isotype (IgG/IgA/IgE) production. In some cases, CSR deficiencies can be associated with abnormal somatic hypermutation. Analysis of CSR deficiencies has helped reveal the key functions of CSR-triggering molecules, i.e., CD40L, CD40, and effector molecules such as activation-induced cytidine deaminase and uracil N-glycosylase. We report a new form of B cell-intrinsic CSR deficiency found in three patients with deleterious, homozygous mutations in the gene encoding the PMS2 component of the mismatch repair machinery. CSR was found partially defective in vivo and markedly impaired in vitro. It is characterized by the defective occurrence of double-strand DNA breaks (DSBs) in switch regions and abnormal formation of switch junctions. This observation strongly suggests a role for PMS2 in CSR-induced DSB generation. | 18,824,584 |
The Amot/Patj/Syx signaling complex spatially controls RhoA GTPase activity in migrating endothelial cells. | Controlled regulation of Rho GTPase activity is an essential component mediating growth factor-stimulated migration. We have previously shown that angiomotin (Amot), a membrane-associated scaffold protein, plays a critical role during vascular patterning and endothelial migration during embryogenesis. However, the signaling pathways by which Amot controls directional migration are not known. Here we have used peptide pull-down and yeast 2-hybrid (Y2H) screening to identify proteins that interact with the C-terminal PDZ-binding motifs of Amot and its related proteins AmotL1 and 2. We report that Amot and its related proteins bind to the RhoA GTPase exchange factor (RhoGEF) protein Syx. We show that Amot forms a ternary complex together with Patj (or its paralogue Mupp1) and Syx. Using FRET analysis, we provide evidence that Amot controls targeting of RhoA activity to lamellipodia in vitro. We also report that, similar to Amot, morpholino knockdown of Syx in zebrafish results in inhibition of migration of intersegmental arteries. Taken together, our results indicate that the directional migration of capillaries in the embryo is governed by the Amot:Patj/Mupp1:Syx signaling that controls local GTPase activity. | 18,824,598 |
Commercial sex and HIV transmission in mature epidemics: a study of five African countries. | The study compares the association between using the services of commercial sex workers and male HIV seroprevalence in five African countries: Ghana, Kenya, Lesotho, Malawi and Rwanda. The HIV seroprevalence among men who 'ever paid for sex' was compared with controls who 'never paid for sex'. Results were based on 12,929 eligible men, aged 15-59 years, interviewed in Demographic and Health Surveys. The odds ratio of HIV seroprevalence associated with ever paying for sex was 1.89 (95% confidence interval = 1.57-2.28), with only minor differences by country. The results were stable in multivariate analysis after controlling for available potential cofactors (data on non-sexual routes of transmission were not available). Given the relatively small proportion of men involved, the risk attributable to 'ever paying for sex' remained low: 7.1% in univariate analysis and 4.4% after adjustment, and it varied among countries (range 1.3-9.4%). These results match previous observations that commercial sex seems to play a minor role in the spread of HIV in mature epidemics. | 18,824,616 |
Syphilis causing hearing loss. | An HIV-positive man with hepatitis B co-infection, naïve to highly active antiretroviral therapy, with a CD4 of 594 copies/mL and HIV-1 viral load of 140,070 copies, presented with right-sided facial weakness and hearing loss. He had been treated for secondary syphilis three months earlier when his rapid plasma reagin (RPR) result was 1:16, this had fallen to neat. At presentation, his RPR had risen to 1:16 again. A magnetic resonance imaging scan showed enhancement of the internal auditory canal and right cochlea. His cerebrospinal fluid examination was normal. He was treated with acyclovir and prednisolone before the syphilis serology was known. He was then treated for syphilis with doxycycline. He made an excellent recovery. | 18,824,631 |
Nitric oxide upregulates dimethylarginine dimethylaminohydrolase-2 via cyclic GMP induction in endothelial cells. | Dimethylarginine dimethylaminohydrolase (DDAH) is an enzyme that metabolizes asymmetrical N(G),N(G)-dimethyl-L-arginine (ADMA) and N(G)-monomethyl-L-arginine (MMA), which are competitive endogenous inhibitors of NO synthase. However, it remains unknown whether NO itself influences DDAH activity and/or ADMA/MMA contents to regulate NO generation via a biofeedback mechanism. The present study was designed to examine the effects of NO on intracellular ADMA and MMA contents and DDAH gene expression levels and enzymatic activities in cultured rat aortic endothelial cells. The NO donors SNAP and NOR3 did not influence DDAH-1 expression but increased DDAH-2 mRNA and protein levels in concentration-dependent manners. SNAP upregulated DDAH enzymatic activity and reduced the MMA and ADMA contents but did not affect the symmetrical N(G),N'(G)-dimethyl-L-arginine and L-arginine levels, thereby negating a mediatory role for system y(+) in ADMA/MMA downregulation. The cGMP agonists 8-bromo-cGMP and C-type natriuretic peptide also stimulated DDAH-2 gene and protein expression levels and DDAH activity and increased the amount of nitrite/nitrate released into the culture supernatants. SNAP-induced DDAH-2 gene expression and DDAH activity were significantly inhibited by a protein kinase G inhibitor, KT5823, and a soluble guanylate cyclase inhibitor, ODQ, suggesting a mediatory role for cGMP in NO-induced DDAH-2 expression. Suppression of DDAH-2 mRNA using small interfering RNA technology abrogated NO-induced DDAH-2 expression. These data demonstrate that NO acts on endothelial cells to induce DDAH-2 expression via a cGMP-mediated process to reduce ADMA/MMA. Thus, the DDAH-2-ADMA/MMA-endothelial NO synthase regulatory pathway and NO-induced cGMP constitute a positive feedback loop that ultimately serves to maintain NO levels in the endothelial environment. | 18,824,664 |
The "Cheshire Cat" escape strategy of the coccolithophore Emiliania huxleyi in response to viral infection. | The coccolithophore Emiliania huxleyi is one of the most successful eukaryotes in modern oceans. The two phases in its haplodiploid life cycle exhibit radically different phenotypes. The diploid calcified phase forms extensive blooms, which profoundly impact global biogeochemical equilibria. By contrast, the ecological role of the noncalcified haploid phase has been completely overlooked. Giant phycodnaviruses (Emiliania huxleyi viruses, EhVs) have been shown to infect and lyse diploid-phase cells and to be heavily implicated in the regulation of populations and the termination of blooms. Here, we demonstrate that the haploid phase of E. huxleyi is unrecognizable and therefore resistant to EhVs that kill the diploid phase. We further show that exposure of diploid E. huxleyi to EhVs induces transition to the haploid phase. Thus we have clearly demonstrated a drastic difference in viral susceptibility between life cycle stages with different ploidy levels in a unicellular eukaryote. Resistance of the haploid phase of E. huxleyi provides an escape mechanism that involves separation of meiosis from sexual fusion in time, thus ensuring that genes of dominant diploid clones are passed on to the next generation in a virus-free environment. These "Cheshire Cat" ecological dynamics release host evolution from pathogen pressure and thus can be seen as an opposite force to a classic "Red Queen" coevolutionary arms race. In E. huxleyi, this phenomenon can account for the fact that the selective balance is tilted toward the boom-and-bust scenario of optimization of both growth rates of calcifying E. huxleyi cells and infectivity of EhVs. | 18,824,682 |
Caulobacter requires a dedicated mechanism to initiate chromosome segregation. | Chromosome segregation in bacteria is rapid and directed, but the mechanisms responsible for this movement are still unclear. We show that Caulobacter crescentus makes use of and requires a dedicated mechanism to initiate chromosome segregation. Caulobacter has a single circular chromosome whose origin of replication is positioned at one cell pole. Upon initiation of replication, an 8-kb region of the chromosome containing both the origin and parS moves rapidly to the opposite pole. This movement requires the highly conserved ParABS locus that is essential in Caulobacter. We use chromosomal inversions and in vivo time-lapse imaging to show that parS is the Caulobacter site of force exertion, independent of its position in the chromosome. When parS is moved farther from the origin, the cell waits for parS to be replicated before segregation can begin. Also, a mutation in the ATPase domain of ParA halts segregation without affecting replication initiation. Chromosome segregation in Caulobacter cannot occur unless a dedicated parS guiding mechanism initiates movement. | 18,824,683 |
Kinetic regulation of coated vesicle secretion. | The secretion of vesicles for intracellular transport often relies on the aggregation of specialized membrane-bound proteins into a coat able to curve cell membranes. The nucleation and growth of a protein coat is a kinetic process that competes with the energy-consuming turnover of coat components between the membrane and the cytosol. We propose a generic kinetic description of coat assembly and the formation of coated vesicles and discuss its implication to the dynamics of COP vesicles that traffic within the Golgi and with the endoplasmic reticulum. We show that stationary coats of fixed area emerge from the competition between coat growth and the recycling of coat components, in a fashion resembling the treadmilling of cytoskeletal filaments. We further show that the turnover of coat components allows for a highly sensitive switching mechanism between a quiescent and a vesicle producing membrane, upon a slowing down of the exchange kinetics. We claim that the existence of this switching behavior, also triggered by factors, such as the presence of cargo and variation of the membrane mechanical tension, allows for efficient regulation of vesicle secretion. We propose a model, supported by different experimental observations, in which vesiculation of secretory membranes is impaired by the energy-consuming desorption of coat proteins, until the presence of cargo or other factors triggers a dynamical switch into a vesicle producing state. | 18,824,695 |
Association between hepatitis B virus and pancreatic cancer. | Hepatitis B virus (HBV) and hepatitis C virus (HCV) are considered to be hepatotropic and are a major cause of hepatocellular carcinoma. However, little is known about the role of HBV and HCV infection in other malignancies. This study aimed to determine whether HBV and HCV infections increase the risk for pancreatic cancer development. At The University of Texas M. D. Anderson Cancer Center, Houston, TX, we recruited 476 patients with pathologically confirmed adenocarcinoma of the pancreas and 879 age-, sex-, and race-matched healthy controls. Blood samples were tested for the presence of HCV antibodies (anti-HCV), HBV surface antigen (HBsAg), antibodies against HBV core antigen (anti-HBc), and antibodies against HBsAg (anti-HBs). The positive samples were retested by two confirmatory tests. An unconditional multivariable logistic regression analysis was used to estimate adjusted odds ratios (AORs). Anti-HCV was positive in seven cases (1.5%) and nine controls (1%). Anti-HBc was positive in 36 cases (7.6%) and 28 controls (3.2%). The estimated AORs and 95% CIs were as follows: anti-HCV-positive, 0.9 (95% CI, 0.3 to 2.8), anti-HBc-positive, 2.5 (95% CI, 1.5 to 4.2), anti-HBc-positive/anti-HBs-positive, 2.3 (95% CI, 1.2 to 4.2), and anti-HBc-positive/anti-HBs-negative, 4 (95% CI, 1.4 to 11.1). Risk modification by past exposure to HBV was observed among diabetics (AOR, 7.1; 95% CI, 1.7 to 28.7). Past exposure to HBV may be associated with pancreatic cancer development. Should such findings be confirmed by other studies, it may offer important insights into the etiology of pancreatic cancer and may suggest the need to consider prevention of HBV reactivation among patients with HBV-related pancreatic cancer during chemotherapy. | 18,824,707 |
Availability and use of palliative care and end-of-life services for pediatric oncology patients. | Palliative care prevents or relieves the symptoms caused by life-threatening medical conditions. Previous surveys have shown both underuse and lack of availability of these services for children with cancer throughout North America. We sought to investigate the current practices and resources surrounding palliative and end-of-life care among participating institutions of the Children's Oncology Group (COG). A survey regarding practices and resources was developed by the COG palliative care subcommittee and was sent to all 232 institutions to complete for the calendar year 2005. The survey was completed by 81% of the institutions. Per institution, there were a mean of 64.6 newly diagnosed patients and 17.7 patients experiencing relapse. A palliative care team was available in 58% of institutions, a pain service in 90%, a hospice in 60%, a psychosocial support team in 80%, and a bereavement program in 59%. Complementary and alternative medicine was available in 39% of institutions and in 95% of the COG institution's community. Most services, even when available, were not well used by patients. Despite the well-established benefit of pediatric palliative care, it is only offered in 58% of COG institutions caring for children with cancer. In an era where the benefit of palliative care has been clearly established, this number should approach 100%. Efforts should be directed toward understanding barriers to provision of such services, so that they are available and well used at all childhood cancer centers. | 18,824,711 |
Mucosal IgA increase in rats by continuous CLA feeding during suckling and early infancy. | The aim of this work was to establish the effect of the cis9,trans11 conjugated linoleic acid (CLA) isomer on mucosal immunity during early life in rats, a period when mucosal immunoglobulin production is poorly developed, as is also the case in humans. CLA supplementation was performed during three life periods: gestation, suckling, and early infancy. The immune status of supplemented animals was evaluated at two time points: at the end of the suckling period (21-day-old rats) and 1 week after weaning (28-day-old rats). Secretory IgA was quantified in intestinal washes from 28-day-old rats by ELISA technique. IgA, TGFbeta, and PPARgamma mRNA expression was measured in small intestine and colon by real time PCR, using Taqman specific probes and primers. IgA mucosal production was enhanced in animals supplemented with CLA during suckling and early infancy: in 28-day-old rats, IgA mRNA expression was increased in small intestine and colon by approximately 6- and 4-fold, respectively, and intestinal IgA protein by approximately 2-fold. TGFbeta gene expression was independent of age and type of tissue considered, and was not modified by dietary CLA. Gene expression of PPARgamma, a possible mediator of CLA's effects was also upregulated in animals receiving CLA during early life. In conclusion, dietary supplementation with CLA during suckling and extended to early infancy enhances development of the intestinal immune response in rats. | 18,824,724 |
Upper and lower tear menisci on contact lenses. | The purpose of this study was to measure upper and lower tear menisci on contact lenses using real time optical coherence tomography (OCT). Both eyes of 20 adapted contact lens wearers were imaged when they wore two types of silicone hydrogel lenses, balafilcon A on one eye and galyfilcon A on the other eye. The height, radius, and area of upper and lower tear menisci were obtained before, immediately after, and 20 minutes after lens wear on two consecutive days. On a third visit, the lenses were switched between eyes and an investigative lubricant was instilled after 4 hours of lens wear. OCT images were obtained as before and additionally at 1 and 4 hours after lens insertion. Imaging was also conducted immediately after lubricant instillation and 20 minutes post-instillation. There were no significant differences in the measured variables between lenses (P > 0.05) and between consecutive visits (P > 0.05). The menisci around both eyelids immediately after lens insertion were significantly greater than that before (P < 0.005). By 20 minutes after lens insertion, all variables had returned to baseline values and remained that way for at least 4 hours. Immediately after the instillation of the lubricant at 4 hours, meniscus variables increased (P < 0.001), but recovery to baseline occurred within 20 minutes. It is feasible to use OCT in the measurement of both upper and lower tear menisci on contact lenses in situ. Tear menisci increased on insertion of contact lenses and on instillation of lubricants. However baseline values were re-established with 20 minutes. | 18,824,725 |
Rod and rod-driven function in achromatopsia and blue cone monochromatism. | To evaluate rod photoreceptor and postreceptor retinal function in pediatric patients with achromatopsia (ACHR) and blue cone monochromatism (BCM) using contemporary electroretinographic (ERG) procedures. Fifteen patients (age range, 1-20 years) with ACHR and six patients (age range, 4-22 years) with BCM were studied. ERG responses to full-field stimuli were obtained in scotopic and photopic conditions. Rod photoreceptor (S(rod), R(rod)) and rod-driven postreceptor (log sigma, V(max)) response parameters were calculated from the a-wave and b-wave. ERG records were digitally filtered to demonstrate the oscillatory potentials (OPs); a sensitivity parameter, log SOPA(1/2), and an amplitude parameter, SOPA(max), were used to characterize the OP response. Response parameters were compared with those of 12 healthy control subjects. As expected, photopic responses were nondetectable in patients with ACHR and BCM. In addition, mean scotopic photoreceptor (R(rod)) and postreceptor (V(max) and SOPA(max)) amplitude parameters were significantly reduced compared with those in healthy controls. The flash intensity required to evoke a half-maximum b-wave amplitude (log sigma) was significantly increased. Results of this study provide evidence that deficits in rod and rod-mediated function occur in the primary cone dysfunction syndromes ACHR and BCM. | 18,824,728 |
Tight heart rate control reduces secondary adverse events in patients with type B acute aortic dissection. | Although type B aortic dissection has been treated with beta blockers to lower the arterial blood pressure (BP), there has been little evidences about reduction in heart rate (HR). We assessed whether tight HR control improved the outcome of medical treatment in patients with aortic dissection. From 1997 to 2005, 171 patients with acute aortic dissection medically treated and controlled to lower BP under 120 mm Hg were enrolled. Based on the average HR at 3, 5, and 7 days after the onset, patients were divided into tight HR (<60 beat per minute) control group (32 patients; mean HR of 56.6+/-3.1 beat per minute) and conventional HR (>/=60 beat per minute) control group (139 patients; mean HR of 71.7+/-8.2 beat per minute). We compared the frequency of aortic events including late organ or limb ischemia, aortic rupture, recurrent dissection, and aortic expansion of >5 mm, and surgical requirement between two groups. During a median follow-up of 27.0 months, late organ or limb ischemia, aortic rupture, recurrent dissection, pathological aortic expansion, and aortic surgery occurred in 0, 8, 14, 39, and 26 patients, respectively. Reduction in aortic events was observed in tight HR control group (12.5%) compared to conventional HR control group (36.0%), (Odds ratio: 0.25, C.I.: 0.08 to 0.77, P<0.01). The present study demonstrated that tight heart rate control improved the outcome of medical treatment in patients with aortic dissection. | 18,824,750 |
Survival after resection of primary cardiac tumors: a 48-year experience. | Primary cardiac tumors are rare but have the potential to cause significant morbidity if not treated in an appropriate and timely manner. To date, however, there have been no studies examining survival characteristics of patients who undergo surgical resection. From 1957 to 2006, 323 consecutive patients underwent surgical resection of primary cardiac tumors; 163 (50%) with myxomas, 83 (26%) with papillary fibroelastomas, 18 (6%) with fibromas, 12 (4%) with lipomas, 28 (9%) with other benign primary cardiac tumors, and 19 (6%) with primary malignant tumors. Operative (30 day) mortality was 2% (n=6). Univariate analysis indicated that patients who underwent resection of fibromas and myxomas had superior survival characteristics in comparison to the remainder of tumor variants; these results were consistent after adjusting for age at surgery, year of surgery, and cardiovascular risk factors. Based on actuarial characteristics of the 2002 U.S. population, patients who underwent myxoma resection had survival characteristics that were not significantly different from that of an age and gender matched population (SMR 1.11, P=0.57) whereas those who underwent resection of fibromas (SMR 11.17, P=0.002), papillary fibroelastomas (SMR 3.17, P=0.0003), lipomas (SMR 5.0, P=0.0003), other benign tumors (SMR 4.63, P=0.003), and malignant tumors (SMR 101, P<0.0001) had significantly poorer survival characteristics. Furthermore, malignant tumors in younger patients were highly fatal (HR 0.899, P<0.0001). Although the most significant predictor of mortality was tumor histology, survival was also influenced the by the duration of CPB and NYHA III/IV; the impact of these risk factors varied with time. The cumulative incidence of myxoma recurrence was 13% and occurred in a younger population (42 versus 57 years, P=0.003) with the risk of recurrence decreased after 4 years. Surgical resection of primary cardiac tumors is associated with excellent long-term survival; patients with cardiac myxomas have survival characteristics that are not significantly different from that of a general population. Predictors of mortality are primarily related to tumor histology but also include clinical characteristics such as symptomatology and duration of CPB. | 18,824,772 |
CCR2-mediated antiinflammatory effects of endothelial tetrahydrobiopterin inhibit vascular injury-induced accelerated atherosclerosis. | Vascular injury results in loss of endothelial nitric oxide (NO), production of reactive oxygen species (ROS), and the initiation of an inflammatory response. Both NO and ROS modulate inflammation through redox-sensitive pathways. Tetrahydrobiopterin (BH4) is an essential cofactor for endothelial nitric oxide synthase (eNOS) that regulates enzymatic synthesis of either nitric oxide or ROS. We hypothesized that endothelial BH4 is an important regulator of inflammation and vascular remodeling. Endothelium-targeted overexpression of GTP cyclohydrolase 1 (GCH), the rate limiting enzyme in BH4 synthesis, increased levels of tetrahydrobiopterin (BH4), reduced endothelial superoxide, improved eNOS coupling, and reduced vein graft atherosclerosis in transgenic GCH/ApoE-KO mice compared to ApoE-KO controls. Immunohistochemistry using anti-MAC-3 and MAC-1 antibody staining revealed a marked reduction in vein graft macrophage content, as did RT-PCR expression of macrophage marker CD68 mRNA levels in GCH/ApoE-KO mice. When we investigated the potential mediators of this reduction, we discovered that mRNA and protein levels of MCP-1 (CCL2) but not RANTES (CCL5) were significantly reduced in GCH/ApoE-KO aortic tissue. Consistent with this finding we found a decrease in CCR2-mediated, but not CCR5-mediated, chemotaxis in vascular tissue and plasma samples from GCH/ApoE-KO animals. Increased endothelial BH4 reduces vein graft neointimal hyperplasia and atherosclerosis through a reduction in vascular inflammation. These findings highlight the importance of MCP-1/CCR2 signaling in the response to vascular injury and identify novel pathways linking endothelial BH4 to inflammation and vascular remodeling. | 18,824,773 |
Hydrological analysis of single and dual storage systems for stormwater harvesting. | As stormwater flows are intermittent, the requirement to store urban runoff is important to the design of a stormwater re-use scheme. In many urban areas, the space available to provide storage is limited and thus the need to optimise the storage volume becomes critical. This paper will highlight the advantages and disadvantages of two different approaches of providing storage: 1) a single shallow storage (0.5 m depth) in which stormwater capture and a balanced release to supply users is provided by the one unit; and 2) a dual system in which the functions of stormwater capture and supply release are provided by two separate deeper storage units (2 m depth). The comparison between the two strategies is supported by water balance modelling assessing the supply reliability and storage volume requirements for both options. Above a critical volumetric capacity, the supply yield of a dual storage system is higher than that from a single storage of equal volume mainly because of a smaller assumed footprint. The single storage exhibited greater evaporation loss and is more susceptible to algae blooms due to long water residence times. Results of the comparison provide guidance to the design of more efficient storages associated with stormwater harvesting systems. | 18,824,802 |
Pretreatment of wastewater containing a mixture of organic pollutants obtained from a CC2 plant by coagulation. | Coagulation is one of the most important physicochemical treatment steps in industrial wastewater to reduce the suspended and colloidal materials responsible for colour and turbidity of the wastewater. The manufacturing plant of N,N'-Dichloro bis (2,4,6-trichlorophenyl) urea (CC2) produces wastewater containing pyridine, acetic acid and diphenyl urea (DPU). The wastewater also contains lot of suspended solids like CC2 and various poly-aromatic compounds. In our present investigation, our basic aim was to find an effective coagulation process for the pretreatment of wastewater discharged from the CC2 plant. Studies were conducted to find out a suitable and effective coagulant for pretreatment of this wastewater. Various coagulating agents such as alum, ferric chloride, sodium carboxymethyl cellulose (Na-CMC) were used. Alum was found to be the most effective coagulant. Coagulation of the wastewater resulted in the total suspended solids (TSS) removal in the range of 92-94% and chemical oxygen demand (COD) removal in the range of 59 to 65% at a dose of 500 mg L(-1) of alum at a pH>or=7.0. After coagulation the concentration of pyridine in wastewater was found to be reduced by 10.0% and that of DPU 40-45% with a dosage of 500 mg L(-1) alum. | 18,824,806 |
Global issues related to the impact of untreated attention-deficit/hyperactivity disorder from childhood to young adulthood. | Attention-deficit/hyperactivity disorder (ADHD) is a common, chronic, and costly disorder, with an impact that can span from preschool into adulthood. There are safe and effective therapies that can manage and help prevent many of the associated negative outcomes of ADHD, but treatment rates are far from optimal and considerable obstacles exist in achieving satisfactory treatment adherence. Individuals with untreated ADHD, their families, and other caregivers must be made aware of the impact that this disorder may have on them at every stage of life and, correspondingly, the improved outcomes that can be achieved with the successful management of ADHD. | 18,824,825 |
Comparison of the Sensititre YeastOne colorimetric antifungal panel with the modified Clinical and Laboratory Standards Institute broth microdilution (M38-A) method for antifungal susceptibility testing of dermatophytes. | To compare the susceptibility of different dermatophyte species to itraconazole (I), fluconazole (F) and voriconazole (V) by the modified reference (microdilution, CLSI M38-A) and the colorimetric method Sensititre YeastOne. The microdilution method is not very practical for use in routine susceptibility testing in the clinical laboratory, thus necessitating the use of other methods. We studied a total of 46 dermatophyte strains isolated from clinical specimens. The microdilution reference susceptibility testing was performed following the CLSI M38-A document, using I, F and V drugs. The MIC were defined as the lowest drug concentration that produced 100% (I and V) and 50% inhibition (F) after 72 h incubation at 35 degrees C. The Sensititre MIC were detected by a change in color from pink to blue or purple. Agreement levels between the 2 methods (+/-2 dilutions) for I, F and V were 30, 53.3 and 83.3%, 0, 12.5 and 66.6% and 37.5, 44.4 and 75% for Trichophyton mentagrophytes, Trichophyton rubrum and Microsporumgypseum, respectively. The MIC(50/90) (mg/l) of I, F and V for T. mentagrophytes were 0.25/0.5, 16/64 and 0.12/0.25 by the microdilution method and 0.016/0.06, 8/16 and 0.03/0.06 by the Sensititre method. The MIC for I, F and V for T. rubrum were 0.25/1, 8/64 and 0.25/0.5 by the microdilution and 0.008/0.03, 2/8, 0.016/0.03 by the Sensititre method. For M. gypseum, MIC were 0.5/1 (I), /256 (F) and 0.25/1 (V) as well as 0.016/0.25 (I), 16/256 (F) and 0.06/0.25 (V) by the microdilution and Sensititre methods, respectively. The MICs obtained were lower by the Sensititre than the microdilution method. The best correlation between both methods was obtained for V in T. mentagrophytes (>80%), but was low for T. rubrum. Although the Sensititre method is easy to use in a clinical laboratory, it shows poor agreement with the reference method for dermatophytes. | 18,824,849 |
Hashimoto's thyroiditis in Down's syndrome: clinical presentation and evolution. | It was the aim of this study to describe the presentation and clinical course of Hashimoto's thyroiditis (HT) in children with Down's syndrome (DS) in 2 Scottish health regions. We retrospectively analysed clinical, biochemical and thyroid antibody status in 38 patients with DS with HT diagnosed from 1989 to 2004. The sex distribution was similar (20 males, 18 females), with a median age of 12.3 years (range 2.1-17.7). Of the 38 patients reviewed, 29 were identified by screening. A goitre was present in 6/38 patients. Thyroid antibodies were positive in 36/38 patients, negative in 1/38, and data were unavailable for 1/38. At presentation, 37/38 patients were hypothyroid: 21/37 with compensated hypothyroidism (6 treated initially) and 16/37 with decompensated hypothyroidism (all treated). Of the 15/21 compensated patients who were untreated initially, only 3 remitted while 12 showed disease progression prompting treatment. In the decompensated group, 1/16 patient pursued a fluctuating course between hypo- and hyperthyroidism. The final patient, who was hyperthyroid at presentation, also showed marked fluctuation in thyroid function over a 5-year period. The natural history of HT in DS is unusual, with no female predominance and infrequent goitre in our cohort. While almost all patients required treatment eventually, clinicians should be aware that the disease may pursue a fluctuating course between hypo- and hyperthyroidism. | 18,824,866 |
Nitric oxide involvement in TNF-alpha and IL-1 beta-mediated changes in human mesangial cell MMP-9 and TIMP-1. | Mesangial cells are known to secrete metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) that are capable of disrupting the glomerular basement membrane (GBM). Disruption of the GBM appears to be an important mechanism in the renal disease process, however little is known about the mechanisms involved. Therefore we examined the potential role of nitric oxide (NO) in the regulation of MMP-9 and TIMP-1 by tumour necrosis factor-alpha (TNF-alpha) and interleukin-1 beta (IL-1 beta) using the human mesangial cell line (HMCL). The HMCL was treated with various concentrations of cytokines and NO inhibitors. Activity of MMP-9 was examined by gelatin zymography and TIMP-1 expression was analysed by Western blotting. NO production was measured using the Greiss assay. In this study, stimulation of HMCL cells with TNF-alpha or IL-1 beta, alone or in combination, led to a substantial increase in NO production, which was shown to result from an increase in the expression of the inducible form of NOS (iNOS). Treatment of cells with the specific iNOS inhibitor L-NIL potentiated the increase in MMP-9 production induced by TNF-alpha, but prevented the suppression of TIMP-1 production observed following cytokine treatment. The NO donor, sodium nitroprusside, also stimulated a substantial increase in NO production in HMCL cells, which was associated with a reduction in basal and TNF-alpha-stimulated MMP-9 and a potentiation of the cytokine-induced decrease in TIMP-1. Our study provides convincing evidence of a modulatory role for NO on cytokine-induced MMP-9 and TIMP-1 production in human mesangial cells. | 18,824,875 |
Marker development for erect versus pendant-orientated fruit in Capsicum annuum L. | The erect habit of fruit setting is a unique characteristic of ornamental peppers and wild pepper species. The erect habit is known to be controlled by the up locus on pepper (Capsicum annuum L.) chromosome 12. The result of a genetic analysis using Saengryeog 211 (pendant), Saengryeog 213 (erect), and their F1 and BC1 progeny demonstrated that up is a recessive gene. To develop an up-linked marker, bulked segregant analysis (BSA) and amplified fragment length polymorphism (AFLP) were employed using 108 F2:3 individuals. The closest AFLP marker, A2C79, was located at a genetic distance of 1.7 cM from the up locus and was converted into a cleaved amplified polymorphic sequence (CAPS) marker. This marker was mapped at a genetic distance of 4.3 cM from the up locus. When the CAPS was applied to seven ornamental lines and 27 breeding lines with erect fruit, these genotypes of 28 lines were correctly predicted. Thus, the CAPS marker will be useful for marker-assisted selection (MAS) of pepper breeding lines with the up allele at the early seedling stage. | 18,824,887 |
Treatment-related risk factors for hospital mortality in Candida bloodstream infections. | To examine the relationship between treatment-related variables for Candida bloodstream infection and hospital mortality. Retrospective cohort analysis. Thousand two hundred-bed academic medical center. A total of 245 consecutive patients with Candida bloodstream infections who received antifungal therapy. Identification of treatment-related risk factors: central vein catheter retention, inadequate initial fluconazole dosing, and delayed administration of antifungal therapy. A total of 245 patients with Candida bloodstream infections who received antifungal therapy were identified. One hundred eleven (45.3%) patients were managed in an intensive care unit and analyzed as a separate subgroup. In the hospital cohort, 72 (29.4%) patients died during hospitalization and 40 (36.0%) patients died in the intensive care unit cohort. In the hospital cohort, logistic regression analysis identified Acute Physiology and Chronic Health Evaluation II scores (1-point increments) (adjusted odds ratio [AOR], 1.18; 95% confidence interval [CI], 1.11-1.25; p = 0.003), corticosteroid use at the time a positive blood culture was drawn (AOR, 3.41; 95% CI, 1.96-5.93; p = 0.027), inadequate initial fluconazole dosing (AOR, 3.31; 95% CI, 1.83-6.00; p = 0.044), and retention of a central vein catheter (AOR, 4.85; 95% CI, 2.54-9.29; p = 0.015) as independent determinants of hospital mortality. In the intensive care unit cohort, logistic regression analysis identified Acute Physiology and Chronic Health Evaluation II scores (1-point increments) (AOR, 1.21; 95% CI, 1.14-1.29; p = 0.001), inadequate initial fluconazole dosing (AOR, 9.22; 95% CI, 2.15-19.79; p = 0.004), and retention of a central vein catheter (AOR, 6.21; 95% CI, 3.02-12.77; p = 0.011), as independent determinants of hospital mortality. For both cohorts the incremental presence of treatment-related risk factors was statistically associated with greater hospital mortality. Treatment-related factors, including retention of central vein catheters and inadequate initial fluconazole dosing, were associated with increased hospital mortality in patients with Candida bloodstream infections. These data suggest that optimization of initial antifungal therapy and removal of central vein catheters may improve the outcomes of patients with Candida bloodstream infections. | 18,824,910 |
Education of patients after whiplash injury: is oral advice any better than a pamphlet? | Randomized parallel-group trial with 1-year follow-up. To evaluate whether education of patients communicated orally by a specially trained nurse is superior to giving patients a pamphlet after a whiplash injury. Long-lasting pain and physical disability after whiplash injuries are related to both serious personal suffering and huge socio-economic costs. Pure educational interventions after such injuries seem generally as effective as more costly interventions, but it is unknown if the way advice is communicated is of any importance. Participants with relatively mild complaints after car collisions were recruited from emergency departments and GPs. A total of 182 participants were randomized to either: (1) a 1 hour-educational session with a specially trained nurse, or (2) an educational pamphlet. Outcome parameters were neck pain, headache, disability, and return to work. Recovery was defined as scoring pain 0 or 1 (0-10 point scale) and not being off sick at the time of the follow-ups. After 3, 6, and 12 months 60%, 58%, and 66%, respectively of the participants had recovered. Group differences were nonsignificant on all outcome parameters, even though the outcome tended to be better for the group receiving personal advice. Prognosis did not differ between patients who received personal education and those who got a pamphlet. However, a systematic tendency toward better outcome with personal communicated information was observed and the question how patients should be educated to reduce the risk of chronicity after whiplash is worth further investigation, since no treatment have been proven to prevent long-lasting symptoms, and all forms of advice or educational therapy are so cheap that even a modest effect justifies its use. | 18,824,949 |
Therapeutic drug monitoring of ziprasidone in a clinical treatment setting. | There is limited information on the pharmacokinetics ofziprasidone (ZIP) in naturalistic clinical settings. The objective of this study was to investigate the concentrations of ZIP and its active metabolite S-methyl-dihydroziprasidone (SMDZ), and the dose-normalized concentrations, using routine therapeutic drug monitoring (TDM) data. A high-performance liquid chromatographic method for determining serum concentrations of these substances for routine clinical use was established at the TDM Laboratory in Linköping, Sweden. This analytical service was available to all physicians in Sweden. Between January 2001 and December 2004, 545 analyses, representing samples from 370 patients, were performed. The median daily ZIP dose was 120 mg (range 20 -320 mg). In all, 121 steady-state trough specimens with essential clinical information were included in the pharmacokinetic evaluation. The median (25th to 75th percentile) serum concentration of ZIP was 125 nmol/L (82-188 nmol/L). The SMDZ:ZIP ratio decreased with increasing serum concentration of ZIP. The median (25th to 75th percentile) dose-normalized concentrations (nmol L(-1) mg(-1) d(-1) forZIPand SMDZ were 1.13 (0.74-1.77) and 0.62 (0.45-0.86), respectively,with SMDZ:ZIP ratio of 0.57 (0.42-0.79). The overall coefficients of variation for dose-normalized serum concentrations of ZIP, SMDZ, andSMDZ:ZIP ratio were 62%, 56%, and 57%, respectively (n = 121). Smoking women had lower normalized ZIP concentrations than nonsmoking women. Twenty-eight patients with repeated eligible TDM analyses were studied for intraindividual variance over time. In summary, great interindividual and intraindividual differences in ZIPconcentrations were observed. TDM of ZIP maybe used for individual dose adjustments and monitoring medication adherence. | 18,824,954 |
The utility of onyx for preoperative embolization of cranial and spinal tumors. | To assess the utility, technical factors, and complications associated with the use of Onyx (Micro Therapeutics, Inc., Irvine, CA) for preoperative embolization of cranial and spinal tumors. We reviewed a prospectively accumulated database for patients in whom Onyx was used for preoperative embolization of cranial and spinal tumors over a 19-month period. The patients' demographic characteristics, tumor type and location, embolic agents used, arteries catheterized, and associated complications were assessed. Specific attention was focused on technical factors associated with the use of Onyx that differed from the use of other commonly used embolic materials. Ten patients (four female and six male; age range, 11-60 yr) underwent preoperative embolization with Onyx before cranial or spinal tumor resection. Tumors included three juvenile nasal angiofibromas, two meningiomas, two hemangioblastomas, two metastases (renal cell and thyroid), and one giant cell tumor. Onyx embolization was performed in 43 vessels over 11 treatment sessions. There were no complications related to the embolization procedures. Deep penetration of the embolic agent into the tumor was documented through preoperative imaging or surgical pathological specimens. Preoperative embolization of cranial and spinal tumors can be performed safely. Specific technical advantages of Onyx included deep penetration of lesions producing extensive tumor infarction, the ability to embolize extensive portions of the tumors through fewer arterial catheterizations, and the safety of catheter withdrawal despite often substantial reflux along the embolic catheter. | 18,824,987 |
Surgical management of unruptured intracranial aneurysms that are inappropriate for endovascular treatment: experience based on two academic centers. | To analyze the results of the surgical management of unruptured intracranial aneurysms (UIA) when coil embolization (CE) was considered first but deemed inappropriate by our multidisciplinary groups. In two institutions, all UIAs recommended for treatment were considered first for a CE procedure if accessibility, neck width, and fundus-to-neck ratio were appropriate. Patients with UIAs considered inappropriate for CE were to undergo a surgical clipping procedure. We reviewed the medical records of all patients who underwent surgical clipping between February 1996 and February 2006. A total of 325 patients with 440 UIAs were treated. Of them, 149 patients were selected by our multidisciplinary staff for treatment by CE, and 176 patients with 238 UIAs were treated by 207 surgical procedures. Angiographic studies revealed complete occlusion in 95% and near total occlusion in 2.5% of surgically treated UIAs. No deaths related to surgery occurred. Sixteen patients (9.1%) experienced postoperative complications, four of which persisted 1 year after surgery (two cases of diplopia and two aphasic disorders). The 1-year morbidity rate was 2.2% (four of 176) by patient and 1.7% (four of 238) by aneurysm. For UIAs smaller than 10 mm in patients younger than 65 years old, the morbidity rate was 0.56%. Our results gathered from two centers with the same management of UIAs show that SC remains a safe and effective treatment for UIAs even when CE is considered first. | 18,824,989 |
The current role of microsurgery for posterior circulation aneurysms: a selective approach in the endovascular era. | During the past decade, management of posterior circulation aneurysms has shifted away from microsurgery. Currently, microsurgical clipping is considered a primary, competitive alternative to endovascular coiling, or more commonly, a secondary alternative when endovascular therapy is unfavorable. We present a large, multidisciplinary team experience with posterior circulation aneurysms in an institution that continues to use microsurgery as a primary treatment modality for selected aneurysms. During a 9-year period, 217 patients with 228 posterior circulation aneurysms were treated microsurgically; they included 106 basilar bifurcation, 27 posterior cerebral artery, 23 superior cerebellar artery, eight anteroinferior cerebellar artery, five basilar trunk, 47 posteroinferior cerebellar artery, and 12 vertebral artery aneurysms. Overall, 81% of patients presented with hemorrhage, and 33% of the aneurysms were large or giant in size. Direct clipping was performed in 75% of cases, and the overall rate of angiographic aneurysm obliteration was 98.1%. Sixteen patients (7.4%) died after surgery, 25 patients (11.5%) experienced transient neurological deterioration, and 17 patients (7.8%) experienced permanent neurological deterioration. At late follow-up (mean duration, 13.6 mo), 144 patients had good outcomes (Glasgow Outcome Scale scores of 5 or 4, 66%), and 184 patients (85%) either improved or were unchanged relative to their preoperative baseline. Overall, mean Glasgow Outcome Scale scores improved from 3.60 to 3.97. Despite increasing reliance on endovascular therapy with posterior circulation aneurysms, there is a role for microsurgical therapy. Microsurgery remains a competitive, primary therapy for superior cerebellar artery, P1 posterior cerebral artery, distal anteroinferior cerebellar artery, and posteroinferior cerebellar artery aneurysms. Microsurgery has become a secondary therapy for P2 posterior cerebral artery, basilar trunk, proximal anteroinferior cerebellar artery, vertebrobasilar junction, and vertebral artery aneurysms when endovascular therapy is unfavorable. The preferred therapy for basilar bifurcation aneurysms remains unclear. Collaborative, multidisciplinary teams are strengthened and results are improved by offering competitive treatment alternatives for patients to consider and select. Rather than abandoning the posterior circulation prematurely, aneurysm surgeons should maintain technical proficiency with these lesions. | 18,824,990 |
Evidence of inflammatory cell involvement in brain arteriovenous malformations. | Brain arteriovenous malformations (AVM) have high matrix metalloproteinase-9, interleukin-6, and myeloperoxidase (MPO) expression, and polymorphic variations in inflammatory genes are associated with an increased risk of hemorrhage. In this study, we characterized the presence of inflammatory cells in AVM lesional tissue specimens. Immunohistochemistry was used to identify and localize neutrophils (MPO as marker), macrophages/microglia (CD68 as marker), T lymphocytes (CD3 as marker), and B lymphocytes (CD20 as marker). Endothelial cell (EC) marker CD31 was used as an index to assess vascular mass (EC mass). Surgical specimens from 20 unruptured, nonembolized AVMs were examined; seven cortical samples from temporal lobectomy were used as controls. Positive signals for inflammatory cell markers were counted and analyzed by normalizing to the area of the tissue section and the amount of endothelial cells (cells/mm/EC mass pixels). Levels of MPO and matrix metalloproteinase 9 were determined by enzyme-linked immunosorbent assay. Neutrophils and macrophages are all frequently identified in the vascular wall of AVM tissue. In contrast, T and B lymphocytes are rarely observed in AVM tissue. AVM tissue displayed more neutrophil and macrophage/microglia markers than epilepsy control tissue (MPO: 434 +/- 333 versus 5 +/- 4, P = 0.0001; CD68: 454 +/- 404 versus 4 +/- 2, P = 0.0001; cells/mm/EC mass pixels). In ex vivo studies, neutrophil quantity, MPO, and matrix metalloproteinase-9 levels were all colinear (R = 0.98-0.99). Our study demonstrates that inflammatory cells are present in AVM tissue. Taken together with previous genetic and cytokine studies, these data are consistent with a novel view that inflammation is associated with AVM disease progression and rupture. | 18,825,001 |
Form follows function: lymphoid tissue microarchitecture in antimicrobial immune defence. | Secondary lymphoid organs (SLOs) are tissues that facilitate the induction of adaptive immune responses. These organs capture pathogens to limit their spread throughout the body, bring antigen-presenting cells into productive contact with their cognate lymphocytes and provide niches for the differentiation of immune effector cells. Therefore, the microanatomy of SLOs defines the ability of an organism to respond to pathogens. SLO microarchitecture is, at the same time, extremely adaptable to environmental changes. In this Review, we discuss recent insights into the function and plasticity of the SLO microenvironment with regards to antimicrobial immune defence. | 18,825,130 |
Are female lower urinary tract symptoms alleviated by alpha-adrenoreceptor antagonists? | This commentary discusses the article by Low and colleagues, who studied the effect of terazosin in women with lower urinary tract symptoms (LUTS) and an International Prostate Symptom Score (IPSS) > o =8. Terazosin therapy significantly improved IPSS quality-of-life scores and King's Health Questionnaire scores. These findings might seem surprising, because previous studies have shown that alpha-adrenoreceptor antagonists are not effective in women with overactive bladder, which is considered the most common form of LUTS in females. Many women have voiding symptoms, however, and the inclusion criteria in this study resulted in a different population profile compared with those of other studies of female LUTS. The mechanism behind the effect of terazosin is unclear. Without urodynamic characterization, it cannot be established whether patients in the study were obstructed, or whether the effect of terazosin was related to a decrease in bladder outflow resistance. | 18,825,132 |
The Boston Acute Stroke Imaging Scale: ready for use in clinical practice? | This Practice Point commentary discusses a report by Torres-Mozqueda et al. on a newly developed classification instrument for predicting outcome after stroke, the Boston Acute Stroke Imaging Scale (BASIS). This tool incorporates imaging data on the patency of the vasculature and the parenchyma and classifies ischemic strokes as major (if large vessels are occluded or parenchymal changes are present) or minor (all others). When testing the scale, the authors looked at short-term outcome at the time of hospital discharge; patients classified with major stroke by BASIS had a higher mortality and longer hospital stay and were more likely to be discharged to a rehabilitation facility than patients with minor stroke. The authors concluded that BASIS can predict outcome after stroke. We point to several shortcomings in the study methodology and argue that, although BASIS has potential as a prognostic tool, further studies are needed before it can be widely used. | 18,825,146 |
Vaccination with dendritic cells pulsed with homogenate protein of spinal cord promotes functional recovery from spinal cord injury in mice. | Randomized, double-blinded animal experiment for neural functional recovery from spinal cord injury (SCI) through vaccination with immature dendritic cells (DCs) pulsed with homogenate protein of spinal cord (hpDCs) in mice. To study the effect of hpDCs in the recovery from SCI in mice. Immature DCs pulsed with homogenate protein of spinal cord, myelin basic protein (MBP) or phosphate-buffer solution (PBS) were injected into spinal cord-injured mice locally or peritoneally. The functional recovery of spinal cord (open-field locomotor rating scale of Basso, Beattie and Bresnahan, BBB score) was measured weekly. The areas of injured region and cyst as well as the thickness of the glial scar were measured and the expressions of glial fibrillary acidic protein, neurofilament and nestin were detected to confirm the BBB scores. Eighty-four days after injection, the BBB score of the hpDCs group (peritoneally injected mice) reached 18.2+/-1.1, significantly higher than that the scores of the mbpDCs and control groups (16.3+/-2.1 and 10.0+/-2.0, respectively). The areas of injured region and cyst as well as the thickness of the glial scar of the hpDCs group were less than that of the control group. Meanwhile, the expression of nestin lasts up to 56 days after injection in the hpDCs group, while it disappeared in the mbpDCs and PBS groups. Implanting DCs pulsed with homogenate protein of spinal cord, but not mbpDCs or PBS alone, locally or peritoneally, have a significant effect on functional recovery and neural preservation from SCI. | 18,825,159 |
Beam propagation factor of partially coherent flat-topped beams in a turbulent atmosphere. | The Wigner distribution function (WDF) has been used to study the beam propagation factor (M(2)-factor) for partially coherent flat-topped (PCFT) beams with circular symmetry in a turbulent atmosphere. Based on the extended Huygens-Fresnel principle and the definition of the WDF, an expression for the WDF of PCFT beams in turbulence has been given. By use of the second-order moments of the WDF, the analytical formulas for the root-mean-square (rms) spatial width, the rms angular width, and the M(2)-factor of PCFT beams in turbulence have been derived, which can be applied to cases of different spatial power spectra of the refractive index fluctuations. The rms angular width and the M(2)-factor of PCFT beams in turbulence have been discussed with numerical examples. It can be shown that the M(2)-factor of PCFT beams in turbulence depends on the beam order, degree of global coherence of the source, waist width, wavelength, spatial power spectrum of the refractive index fluctuations, and propagation distance. | 18,825,195 |
Laser frequency stabilization and control through offset sideband locking to optical cavities. | We describe a class of techniques whereby a laser frequency can be stabilized to a fixed optical cavity resonance with an adjustable offset, providing a wide tuning range for the central frequency. These techniques require only minor modifications to the standard Pound-Drever-Hall locking techniques and have the advantage of not altering the intrinsic stability of the frequency reference. We discuss the expected performance and limitations of these techniques and present a laboratory investigation in which both the sideband techniques and the standard, on-tunable Pound-Drever- Hall technique reached the 100Hz/square root(Hz) level. | 18,825,236 |
Measuring optical tunneling times using a Hong-Ou-Mandel interferometer. | We report a prediction for the delay measured in an optical tunneling experiment using Hong-Ou-Mandel (HOM) interference, taking into account the Goos-Hänchen shift generalized to frustrated total internal reflection situations. We precisely state assumptions under which the tunneling delay measured by an HOM interferometer can be calculated. We show that, under these assumptions, the measured delay is the group delay, and that it is apparently 'superluminal' for sufficiently thick air gaps. We also show how an HOM signal with multiple minima can be obtained, and that the shape of such a signal is not appreciably affected by the presence of the optical tunneling zone, thus ruling out the explanation of the anomalously short tunneling delays in terms of a reshaping of the wavepacket as it goes through the tunneling zone. Finally, we compare the predicted tunneling delay to a relevant classical delay and conclude that our predictions involve no non-causal effect. | 18,825,239 |
Single-mode waveguide optical isolator based on direction-dependent cutoff frequency. | A single-mode-waveguide optical isolator based on propagation direction dependent cut-off frequency is proposed. The isolation bandwidth is the difference between the cut-off frequencies of the lowest forward and backward propagating modes. Perturbation theory is used for analyzing the correlation between the material distribution and the bandwidth. The mode profile determines an appropriate distribution of non-reciprocal materials. | 18,825,259 |
Quantitative spectroscopic imaging for non-invasive early cancer detection. | We report a fully quantitative spectroscopy imaging instrument for wide area detection of early cancer (dysplasia). This instrument provides quantitative maps of tissue biochemistry and morphology, making it a potentially powerful surveillance tool for objective early cancer detection. We describe the design, construction, calibration, and first clinical application of this new system. We demonstrate its accuracy using physical tissue models. We validate its diagnostic ability on a resected colon adenoma, and demonstrate feasibility of in vivo imaging in the oral cavity. | 18,825,262 |
Optical snakes and ladders: dispersion and nonlinearity in microcoil resonators. | Microcoil resonators are a radical new geometry for high Q resonators with unique linear features. In this paper I briefly summarise their linear properties before extending the analysis to nonlinear interactions in microcoil resonators. As expected such nonlinear resonators are bistable and exhibit hysteresis. Finally I discuss possible applications and extensions to such resonators. | 18,825,264 |
Plastinated tissue samples as three-dimensional models for optical instrument characterization. | Histology of biological specimens is largely limited to investigating two-dimensional structure because of the sectioning required to produce optically thin samples for conventional microscopy. With the advent of three-dimensional optical imaging technologies such as optical coherence tomography (OCT), diffuse optical tomography (DOT), and multiphoton microscopy (MPM), methods of tissue preparation that minimally disrupt three-dimensional structure are needed. We propose plastination as a means of transforming tissues into three-dimensional models suitable for optical instrument characterization. Tissues are plastinated by infusing them with transparent polymers, after which they can be safely handled, unlike fresh or fixed tissues. Such models are useful for investigating three-dimensional structure, testing and comparing the performance of optical instruments, and potentially investigating tissue properties not normally observed after the three-dimensional scattering properties of a biological samples are lost. We detail our plastination procedures and show examples of imaging several plastinated tissues from a pre-clinical rat model using optical coherence tomography. | 18,825,267 |
Significant associations of stearoyl-CoA desaturase (SCD1) gene with fat deposition and composition in skeletal muscle. | Gene expression studies in humans and animals have shown that elevated stearoyl-CoA desaturase (SCD1) activity is associated with increased fat accumulation and monounsaturation of saturated fatty acids in skeletal muscle. However, results of the two reported association studies in humans are inconsistent. In the present study, we annotated the bovine SCD1 gene and identified 3 single nucleotide polymorphisms (SNPs) in its 3'untranslated region (UTR). Genotyping these SNPs on a Wagyu x Limousin reference population revealed that the SCD1 gene was significantly associated with six fat deposition and fatty acid composition traits in skeletal muscle, but not with subcutaneous fat depth and percent kidney-pelvic-heart fat. In particular, we confirmed that the high stearoyl-CoA desaturase activities/alleles were positively correlated with beef marbling score, amount of monounsaturated fatty acids and conjugated linoleic acid content, but negatively with amount of saturated fatty acids. The inconsistent associations between human studies might be caused by using different sets of markers because we observed that most associated markers are located near the end of 3'UTR. We found that the proximity of the polyadenylation signal site is highly conserved among human, cattle and pig, indicating that the region might contain functional elements involved in posttranscriptional control of SCD1 activity. In conclusion, our cross species study provided solid evidence to support SCD1 gene as a critical player in skeletal muscle fat metabolism. | 18,825,276 |
Coadsorbed H and CO interaction on platinum. | The behavior of hydrogen near a platinum-surface-adsorbed carbon monoxide molecule is described using a potential energy term constructed from density functional theory. A clear nonattractive interaction of hydrogen with CO is confirmed, most notably with oxygen, which retains its strong H-repulsive traits in the Pt-bound CO case. Inhibiting effects of CO greater than what is expected from simple adsorption site exclusion are discussed with regard to adsorption/desorption and mobility on platinum, as well as possibilities of COH and HCO formation. | 18,825,293 |
[Systemic therapy of metastasizing renal cell carcinoma]. | Once surgical options have been exhausted, systemic therapy is indicated for metastasizing renal cell carcinoma. Until recently this was carried out using mainly immunotherapeutic concepts with unsatisfactory results. Since the majority of clear cell renal cell carcinomas are well vascularised, angiogenetic inhibition offered an alternative therapy goal. To date, four substances have been approved to control angiogenesis in the therapy of renal cell carcinoma: sunitinib, sorafenib, temsirolimus, as well as a combination of bevacizumab and interferon alpha. Other substances, such as everolimus, pazopanib and axitinib, are currently the subject of clinical trials. Initial data on tolerance and efficacy was presented at this years annual conference of the American Society of Clinical Oncology (ASCO). This article examines current therapy options and ASCO data and discusses future trends. | 18,825,295 |
High prevalence of vitamin K and D deficiency and decreased BMD in inflammatory bowel disease. | Vitamin K and D deficiency and decreased bone mineral density (BMD) were highly prevalent in patients with inflammatory bowel disease (IBD), especially Crohn's disease (CD). Dietary intakes of these vitamins, however, were above the Japanese adequate intakes in IBD patients, suggesting that malabsorption is the basis for hypovitaminosis K and D and decreased BMD. We have studied the possible involvement of vitamin K and D deficiency in the pathogenesis of decreased BMD in IBD. Seventy patients with IBD were evaluated for their BMD; plasma levels of vitamin K; phylloquinone (PK), menaquinone-7 (MK-7), and 25OH-D; serum PTH, protein induced by vitamin K absence (PIVKA-II), and undercarboxylated osteocalcin (ucOC) levels; and their food intake. Compared with ulcerative colitis (UC) patients, CD patients had significantly lower plasma vitamin K and 25OH-D concentrations; significantly higher serum levels of PTH, PIVKA-II, and ucOC; and significantly lower BMD scores at almost all measurement sites. More IBD patients were vitamin K deficient in bone than in liver. Multiple regression analyses revealed that low plasma concentrations of vitamin K and 25OH-D were independent risk factors for low BMD and that they were associated with the patients' fat intake, but not with their intake of these vitamins. IBD patients have high prevalence of decreased BMD and vitamin K and D deficiency probably caused by malabsorption of these vitamins. | 18,825,300 |
Peripheral mechanisms I: plasticity of peripheral pathways. | Cough plays a vital role in protecting the lower airways from inhaled irritants, pollutants, and infectious agents. The cough reflex exhibits remarkable plasticity, such that in the context of infectious or inflammatory respiratory diseases such as asthma, chronic bronchitis, and idiopathic pulmonary fibrosis the cough reflex can become dysregulated, leading to a chronic cough. A chronic, nonproductive (dry) cough can rob sufferers of quality of life. Plasticity of the cough reflex likely involves multiple intersecting pathways within the airways, the peripheral nerves that supply them, and the central nervous system. While further studies are needed to determine the presence and relevance of many of these specific pathways in cough associated with chronic respiratory disease, the last decade has yielded unprecedented insight into the molecular identity of the ion channels and associated proteins that initiate and conduct action potentials in the primary sensory nerves involved in reflexes such as cough. We now know, for instance, that members of the transient receptor potential superfamily of nonselective cation channels function as transducers that convert specific external stimuli into neuronal activation. We also know that certain Na+ and K+ channels play specialized roles in regulating action potential discharge in irritant-sensing afferent nerves. In this chapter, we summarize the available information regarding factors that may modulate afferent neuron function acutely, via posttranslational modifications and over the longer term through neurotrophin-dependent alterations of the transcriptional programs of adult sensory neurons. | 18,825,339 |
Central mechanisms II: pharmacology of brainstem pathways. | Following systemic administration, centrally acting antitussive drugs are generally assumed to act in the brainstem to inhibit cough. However, recent work in humans has raised the possibility of suprapontine sites of action for cough suppressants. For drugs that may act in the brainstem, the specific locations, types of neurones affected, and receptor specificities of the compounds represent important issues regarding their cough-suppressant actions. Two medullary areas that have received the most attention regarding the actions of antitussive drugs are the nucleus of the tractus solitarius (NTS) and the caudal ventrolateral respiratory column. Studies that have implicated these two medullary areas have employed both microinjection and in vitro recording methods to control the location of action of the antitussive drugs. Other brainstem regions contain neurones that participate in the production of cough and could represent potential sites of action of antitussive drugs. These regions include the raphe nuclei, pontine nuclei, and rostral ventrolateral medulla. Specific receptor subtypes have been associated with the suppression of cough at central sites, including 5-HT1A, opioid (mu, kappa, and delta), GABA-B, tachykinin neurokinin-1 (NK-1) and neurokinin-2, non-opioid (NOP-1), cannabinoid, dopaminergic, and sigma receptors. Aside from tachykinin NK-1 receptors in the NTS, relatively little is known regarding the receptor specificity of putative antitussive drugs in particular brainstem regions. Our understanding of the mechanisms of action of antitussive drugs would be significantly advanced by further work in this area. | 18,825,342 |
Dissection of the oligogenic resistance to Cucumber mosaic virus in the melon accession PI 161375. | Resistance to Cucumber mosaic virus (CMV) in the exotic melon accession PI 161375, cultivar "Sonwang Charmi" (SC) had previously been described as oligogenic, recessive and quantitative, with a major QTL residing in linkage group XII (LGXII). We have used a collection of near isogenic lines (NILs) with introgressions of SC into the genome of the susceptible accession Piel de Sapo (PS) to further characterise this resistance. Infection of NILs carrying introgressions on LGXII showed that only NIL SC12-1 was resistant to CMV strains P9 and P104.82, but not to strains M6 and TL. Further mapping of this region showed that the resistance, named cmv1 maps in an area of 2.2 cM, between markers CMN61_44 and CMN21_55. Moreover, cmv1 confers total resistance to strains P9 and P104.82, indicating that in these cases it is not quantitative and that cmv1 is sufficient to confer full resistance to these CMV strains. Candidate gene mapping of ten translation initiation factors in the melon genome failed to find any of them in the interval between markers CMN61_44 and CMN21_55. All these results suggest that the resistance to CMV present in SC is oligogenic, where different loci confer resistance to different CMV strains, but not necessarily quantitative, since at least one of these genes (cmv1) confers total resistance, similar to that of the parental SC, and does not need the contribution of other loci. | 18,825,359 |
Evidence for modulation of facial emotional processing bias during emotional expression decoding by serotonergic and noradrenergic antidepressants: an event-related potential (ERP) study. | Serotonergic (SSRI) and noradrenergic (NRI) antidepressants modulate biases in emotional processing such that perceptual bias is shifted away from negative and towards positive emotional material. However, the effects of serotonergic and noradrenergic modulation on the temporal course (occurring in milliseconds) of emotional processing, and in particular, the rapid physiological changes associated with the different stages of emotional processing, are unknown. The current study assessed the effects of acute serotonergic (i.e. with citalopram) and noradrenergic (i.e. with reboxetine) augmentation on event-related potential (ERP) measures associated with 'structural encoding' (N170) and emotion expression decoding (N250 and late positive potential [LPP]) for positive (happy) and negative (sad) facial stimuli relative to neutral facial stimuli. This study employed a double-blind, placebo-controlled, cross-over design in which 12 healthy male participants completed a facial expression recognition task tested under three acute conditions: (a) placebo, (b) citalopram (20 mg) and (c) reboxetine (4 mg). Both citalopram and reboxetine had no effect on the N170 ERP component associated with structural encoding, but potentiated the N250 associated with happy (relative to neutral) emotional facial expression decoding. Both drugs had no valence effects on later ERP measures of emotion expression decoding (LPP). Citalopram and reboxetine have selective effects on the temporal course of emotional processing with evidence to suggest specific effects on emotion expression decoding of positive (happy) emotional facial stimuli as evidenced by changes in the attention-modulated N250 but not structural encoding. These findings provide physiological evidence that antidepressants may shift perceptual biases in emotional processing away from negative and towards positive stimuli. | 18,825,371 |
Serial (1)H-MRS of thalamus during deep brain stimulation of bilateral globus pallidus internus for primary generalized dystonia. | The physiological mechanisms of deep brain stimulation (DBS) are not completely clear. Our understanding of them may be facilitated with the use of proton magnetic resonance spectroscopy ((1)H-MRS). Serial (1)H-MRS of both thalami was performed during the course of DBS of bilateral globus pallidus internus in a patient with primary generalized dystonia. Two days after microelectrode implantation, a pulse frequency of 185 Hz was applied for stimulation. It resulted in relief of symptoms and a decrease of Burke-Fahn-Marsden dystonia rating scale (BFMDRS) scores, and was accompanied by a prominent increase of N-acetylaspartate (NAA)/choline-containing compounds (Cho) ratio, a mild increase of NAA/creatine (Cr) ratio, and a moderate decrease of Cho/Cr ratio. Two weeks later, for a search of the optimal stimulation mode, the pulse frequency was switched to 60 Hz, which resulted in clinical deterioration and significant increase of BFMDRS scores. At that time, all investigated (1)H-MRS-detected metabolic parameters had nearly returned to the pretreatment levels. Use of serial (1)H-MRS investigations of various brain structures during DBS in cases of movement disorders permits detailed evaluation of the treatment response, has a potential for its possible prediction, and may facilitate understanding of the physiological mechanisms of stimulation. | 18,825,378 |
[Rehabilitation and outpatient physiotherapy in rheumatic disease patients. Results of cross-sectional studies of patients with rheumatoid arthritis or ankylosing spondylitis and rheumatologists]. | Rehabilitation and outpatient physiotherapy were investigated from the perspectives of patients suffering from rheumatoid arthritis (RA) or ankylosing spondylitis (AS) and of rheumatologists. In 2007, 204 outpatients with RA and 47 with AS at the Arthritis Center in Halle, Germany, and 117 rheumatologists from all over the country participated in two questionnaire surveys. Patients and rheumatologists gave predominantly positive judgements of physiotherapy, psychological interventions, and patient education programs. However, outpatient care including these interventions was judged to be mainly limited by fixed budgets and other formal restrictions. Even though these therapeutic options are part of (primarily inpatient) rehabilitation programs, the estimate of the need for multidisciplinary rehabilitation programs varied widely among the rheumatologists. Significant objections against rehabilitation include reluctance of the patients, administrative burden for the physicians, payers' rejections, and limited choice of rehabilitation clinic. Despite major functional limitations, a substantial portion of the patients received no multidisciplinary medical rehabilitation, outpatient physiotherapy, psychological interventions, or patient education. Recommendations for the improvement of care are derived from these data. | 18,825,393 |
Four consecutive multicenter phase II trials of adjuvant chemoradiation in patients with completely resected high-risk gastric cancer: the experience of the German AIO/ARO/CAO group. | Feasibility and efficacy of four different adjuvant radiochemotherapy regimens in patients with completely resected gastric cancer were evaluated in consecutive cooperative phase II trials using different 5-fluorouracil (5-FU)-based combination chemotherapies (CTX) and 5-FU-enhanced radiotherapy. Between 2000 and 2005, 157 patients with completely resected gastric adenocarcinoma were included. The study design was based on two cycles of CTX and irradiation with 45 Gy plus concomitant 5-FU 225 mg/m(2) per 24 h between these two cycles. CTX cycles consisted of 5-FU, folinic acid (FA), cisplatin plus paclitaxel (FLPP); 5-FU, FA and cisplatin (FLP); 5-FU, FA and irinotecan (FLI); or 5-FU, cisplatin plus docetaxel (FPD). Median follow-up for all four trials was 18 months (range, 1-64) without significant difference between the four regimens: FLPP 30 months (2-46+), FLP 18 months (1-64+), FLI 15 months (1-26), FPD 10 months (5-19+). Treatment associated toxicity was tolerable and did not differ significantly between the four CTX regimens. Across all patients grade (3/4), toxicities during the first cycle/chemoradiation/second cycle consisted of leukocytopenia 4%/2%/30%, anorexia 5%/10%/6%, diarrhea 6%/1%/3%, nausea 2%/7%/2%. Early death occurred in one patient due to Pneumocystis carinii pneumonia. Median progression free survival was 23 months for FLPP, 18 months for FLP, 14 months for FLI, 9 months for FPD (not significant). One-year-overall survival rates were 95% for FLPP, 82% for FLP, 94% for FLI, 86% for FPD. Adjuvant radiochemotherapy in patients with gastric cancer can be safely given continuous infusion of 5-FU at 225 mg/m(2) per day. In addition, a variety of 5-FU-based multiagent chemotherapy regimen with defined activity in gastric cancer appears both safe and effective when given prior and after radiochemotherapy in this setting. | 18,825,411 |
Dynamics of alpha helix formation in the CSAW model. | We study the folding dynamics of polyalanine (Ala20), a protein fragment with 20 residues whose native state is a single alpha helix. We use the CSAW model (conditioned self-avoiding walk), which treats the protein molecule as a chain in Brownian motion, with interactions that include hydrophobic force and internal hydrogen bonding. We find that large-scale structures form before small-scale structures, and obtain the relevant relaxation times. We find that helix nucleation occurs at two separate points on the protein chain, one near each end. The evolution of small- and large-scale structures involves different mechanisms. While the former can be described by rate equations that govern the growth of helical content, the latter is akin to the relaxation of an elastic solid. | 18,825,424 |
Assessment of organochlorine pesticide levels in Manadas Creek, an urban tributary of the Rio Grande in Laredo, Texas. | The Rio Grande is the natural boundary between the United States and Mexico from El Paso, Texas, to Brownsville, Texas. It supports about 12 million people on both sides of the border for municipal, agricultural, industrial, and recreational uses. The rapid population and economic growth along the border region has led to increased pollution in the Rio Grande, which has been linked to several border health issues associated with pesticide contamination. This project was initiated to assess the organochlorine pesticide levels in the water and sediments in Manadas Creek, an urban tributary of the Rio Grande located in north Laredo, Texas. Water and sediment samples were collected monthly during a 6-month period from July to December of 2006 and analyzed using gas chromatography with an electron capture detector after extraction via a solid-phase microextraction technique. Among the water and sediment samples collected, several organochlorine pesticides including alpha-, beta-, and gamma-hexachlorocyclohexane (HCH), heptachlor epoxide, endrin, and 4,4'-DDT were found in either the creek water or sediments. Analysis of variance results indicated that only gamma-HCH had significant variation in the creek water among the sampling periods. Comparison of results with previous findings showed the presence of higher levels of HCH isomers and much lower DDT concentrations in the present study. | 18,825,443 |
Retraction transaminitis: an inevitable but benign complication of laparoscopic fundoplication. | Transient transaminitis has been identified following laparoscopic abdominal surgery. However, the importance of posture, duration of surgery, and mechanical retraction in its etiology remain unclear. Liver function was assessed preoperatively then at 8, 24, 48 and 72 h following laparoscopic surgery including the following procedures: Nissen fundoplication (LN: n = 10); cholecystectomy (LC: n = 10); inguinal herniorrhaphy (LH: n = 10); and gastrectomy (LG: n = 5). Aspartate aminotransferase (AST) levels in LN patients exhibited a rapid rise within 8 h, peaking at 48 h before returning toward baseline. In the LN group, AST levels were significantly higher at 8 h and 24 hours compared to all other groups and compared to LG at 48 h and 72 h. At 6-week follow-up all AST levels were normal. No significant differences were seen in other hepatic parameters, and no correlation between AST and duration of operation, gender, or age was identified. Antireflux surgery is associated with transaminitis related to hepatic retraction, which is independent of patient posture or duration of observation, and it resolves spontaneously with no clinical consequences. | 18,825,455 |
A one-wire method for anatomic reduction of tibial fractures with Ilizarov frame. | Traditional external fixator techniques do not always correct minor residual malalignment. We asked whether using a one-wire method that corrects minor malalignment with an olive traction wire placed in the plane of the deformity allowed (1) uniform healing, (2) proper alignment, and (3) adequate reduction of fracture gaps. We retrospectively evaluated 72 patients in whom we used closed tibial fracture reduction using a circular external frame. We identified the plane of the residual deformity after alignment on a traction table using a C-arm. In this plane, the final correction was performed with traction through an olive wire. Satisfactory alignment (less than 3 degrees deviation from normal) was obtained in 68 of the 72 patients (94%), and satisfactory reduction (gaps less than 2 mm) attained in 51 (71%). In no case was the fracture site opened surgically. Four patients underwent additional alignment correction with conical washers outside the operating room but no other efforts were needed to obtain further reduction after the initial surgery. Fractures healed in an average of 20 weeks. We observed no major infections. The Ilizarov frame has been a valuable tool to achieve alignment and anatomic or near anatomic reduction of closed tibial fractures. Level IV, therapeutic study. See the Guidelines for Authors for a complete description of levels of evidence. | 18,825,469 |
Darbepoetin in the control of cancer-related anaemia. | A group of 62 patients with different advanced cancers and with an anaemic condition were treated with a short course of darbepoetin administered on two different schedules as supportive therapy. The response rates (i.e. a haemoglobin increase of at least 1 g in 1 month) were 45.7% overall, 52.3% with weekly administration and 39% with 3-weekly administration. Darbepoetin activity was higher in men than in women, in younger patients than in older patients and in moderately anaemic patients than in severely anaemic patients, but these differences were not significant. Darbepoetin administration appears to be useful in rapidly reversing anaemia related to advanced cancer. However, the results reported in the literature for alpha-erythropoietin remain more appealing. | 18,825,479 |
Genetic and phenotypic characterization of a low-pathogenicity avian influenza H11N9 virus. | An H11N9 low-pathogenicity avian influenza virus, A/duck/WA/663/97, was isolated from a sick Mandarin duck kept in an outdoor bird exhibit. Genetic and phenotypic characterization of the virus suggested that it originated from free-flying birds, a concept supported by genetic similarity with waterfowl isolates from the same geographic area and time period. This duck-origin virus had genetic features typical of H11 and N9 viruses, including no neuraminidase stalk deletion, no differences in putative glycosylation sites in either surface protein, and no addition of basic amino acid residues at the hemagglutinin cleavage site compared to published sequences. It replicated in both avian and mammalian cells in vitro, and experimentally challenged chickens developed mild acute upper respiratory lesions but no clinical signs of disease. It elicited immune responses in chickens, resulting in seroconversion in all infected birds, although antibody titers remained low over the experimental period. | 18,825,481 |
Cold co-extraction of hemagglutinin and matrix M1 protein from influenza virus A by a combination of non-ionic detergents allows for visualization of the raft-like nature of the virus envelope. | Membrane solubilization with a mixture of cold non-ionic detergents has been applied to isolate detergent-resistant membranes from intact virus A lipid bilayer. Association of the viral envelope glycoproteins and M1 into a raft lipid-protein complex was verified via detergent insolubility experiments, and the M1:HA stoichiometry of the proposed supramolecular complex was estimated via amino acid analysis. Electron microscopy and dynamic light scattering data revealed that these lipid-protein rafts form unilamellar vesicles with HA spikes on their surfaces similar to influenza virus virions. Together, our data suggest that the cold co-extraction technique visualizes the raft-like nature of the viral envelope and demonstrates the interaction of matrix M1 protein with the envelope. | 18,825,482 |
An examination of dedifferentiation in cognition among African-American older adults. | The structure and organization of cognitive abilities has been examined across the life span. The current analysis had three specific aims: (1) test the factor structure of a broad cognitive ability battery across three age groups; (2) examine differences in the pattern of factor covariation across age groups; and (3) examine the pattern of factor mean differences across age groups. A sample of 512 older African Americans (mean age = 66.6 years, 25.4% male) from the Baltimore Study of Black Aging was administered a battery of cognitive tests assessing the domains of perceptual speed, verbal memory, inductive reasoning, vocabulary, and working memory. Factor models were estimated separately in middle-age adults (50-59 years, n = 107), young-old adults (60-69 years, n = 198), and old-old adults (70-79 years, n = 207). There was loading invariance across the three age groups that suggests that the selected tests measured cognition similarly across age. There was no evidence of dedifferentiation across increasingly older age groups. Factor mean differences were observed with the middle-age group having significantly higher factor means than the young-old and old-old groups; however, there was only one factor mean difference between the young-old and the old-old groups. The results suggest that a pattern of dedifferentiation of cognitive abilities does not exist within this sample of older African Americans and that the 60-69 year age range may be a critical period for cognitive decline in this population. | 18,825,494 |
What, exactly, is cladistics? Re-writing the history of systematics and biogeography. | The development of comparative biology (systematics) has been of interest to philosophers and historians. Particular attention has been placed on the 'war' of the 1970s and 1980s, the apparent dispute among those who preferred this or that methodology. In this contribution we examine the history of comparative biology from the perspective of fundamentals rather than methodologies. Our examination is framed within the artificial-natural classification dichotomy, a viewpoint currently lost from view but worth resurrecting. | 18,825,502 |
Comparison of knowledge and accessibility to information sources of HIV/AIDS between blind and sighted populations in Nigeria. | The aim of this study was to compare the HIV/AIDS knowledge and accessibility to HIV/AIDS information between blind and sighted individuals in Nigeria. A cross-sectional survey was undertaken among rural and urban blind (57) and sighted (62) adolescents in 2006. A structured questionnaire was used to collect data about HIV/AIDS symptoms, transmission and prevention knowledge, as well as accessibility to sources of HIV/AIDS information. Binary logistic regression and chi-square statistics were applied to compare responses between the two populations. Blindness was found to be associated with diminished knowledge of HIV/AIDS transmission, prevention and symptoms. At the same time, the blind rely on different sources of HIV/AIDS information than sighted respondents. A lack of knowledge and limited accessibility to proper sources of information causes the blind disabled to be more vulnerable. It is necessary to supply them with proper information and increase their HIV/AIDS knowledge. | 18,825,516 |
In vitro reactivation of trichlorfon-inhibited butyrylcholinesterase using HI-6, obidoxime, pralidoxime and K048. | Trichlorfon is a specific inhibitor of cholinesterases. It was typically used as an insecticide; however, trichlorfon was described as useful for symptomatic treatment of Alzheimer's disease some years ago. The presented study is aimed at reactivation of trichlorfon-inhibited butyrylcholinesterase since this enzyme play an important role in Alzheimer's disease as deputy for acetylcholinesterase and furthermore it could be applied as a scavenger in case of overdosing. We used in vitro reactivation test for considering only reactivation efficacy of butyrylcholinesterase that is inhibited by trichlorfon and not reactivation of butyrylcholinesterase inhibited by trichlorfon metabolic products. Four reactivators were used: HI-6, pralidoxime, obidoxime, and K048. Although all of the reactivators seem to be effective at 1 mM concentration, a lower concentration was not able ensure sufficient reactivation. There was also an observed lowering of reactivation efficacy when butyrylcholinesterase was exposed to trichlorfon for a longer time interval. | 18,825,528 |
Synthesis and biological activities of new hydrazide derivatives. | The synthesis of a new series of imidazo[1,2-a]pyrazine-2-carboxylic acid arylidene-hydrazides is described. The chemical structures of the compounds were elucidated by IR, (1)H-NMR, FAB(+)-MS spectral data. Their biological activity against various bacteria, fungi species, and Mycobacterium tuberculosis was investigated. Antibacterial activity was measured against Escherichia coli (NRRL B-3704), Staphylococcus aureus (NRRL B-767), Salmonella typhimurium (NRRL B-4420), Proteus vulgaris (NRLL B-123), Enterococcus faecalis (isolated obtained from Faculty of Medicine Osmangazi University, Eskisehir, Turkey), Pseudomonas aeruginosa (NRRL B-23 27853), Klebsiella spp. (isolated obtained from Faculty of Medicine Osmangazi University, Eskisehir, Turkey), while antifungal activity was evaluated against Candida albicans (isolates obtained from Osmangazi Uni. Fac.of Medicine), Candida glabrata (isolates obtained from Osmangazi Uni. Fac.of Medicine). Compounds were also evaluated for antituberculosis activity against Mycobacterium tuberculosis H(37)Rv using the BACTEC 460 radiometric system and BACTEC 12B medium. The compounds showed moderate inhibitor effects against human pathogenic microorganisms., whereas the preliminary results indicated that all of the tested compounds were inactive against Mycobacterium tuberculosis H(37)Rv. | 18,825,530 |
Design, synthesis, characterization and in vitro antimicrobial evaluation of 4,6-diaryl-4,5-dihydro-2-phenyl-2H-indazol-3-ols. | New 4,6-diaryl-4,5-dihydro-2-phenyl-2H-indazol-3-ols 25-32 were designed, synthesized and in vitro microbially evaluated using clinically isolated bacterial strains viz Staphylococcus aureus, beta-Heamolytic streptococcus, Vibreo cholerae, Salmonella typhii, Shigella felxneri and fungal strains viz Aspergillus flavus, Mucor, Rhizopus and Microsporum gypsuem. Results of this study showed that the nature of the substituents on the phenyl rings viz., methyl, methoxy, chloro, nitro as well as the bromo functions at the meta and para positions of the aryl moieties determined the nature and extent of the activity of the fused indazolonol compounds 25-32. | 18,825,556 |
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