title stringlengths 0 1.13k | abstract stringlengths 1 15.7k | PMID int64 22 36.5M |
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Chromatin-modifying enzymes as therapeutic targets--Part 2. | Part 1 of this review described the importance of histone acetylases, deacetylases, methylases and demethylases in transcriptional control and their potential as therapeutic targets. However, precise gene regulation requires the involvement of more than just the addition or removal of acetyl and methyl groups on histones. Histone phosphorylation, ubiquitylation, SUMOylation and poly-ADP-ribosylation, as well as ATP-dependent nucleosome remodeling complexes, play equally pivotal roles in the maintenance of transcriptional fidelity. Accordingly, the enzymes responsible for these modifications are also misregulated in various disease states. To review the complex roles of chromatin-modifying enzymes in gene regulation and to highlight their potential as therapeutic targets. This review is based on recent published literature and online resources. In this second and final part of the review, we discuss the importance of these other histone and nucleosome modifying enzymes in gene transcription as well as their therapeutic potential. | 18,851,700 |
Dynamics of liquids, molecules, and proteins measured with ultrafast 2D IR vibrational echo chemical exchange spectroscopy. | A wide variety of molecular systems undergo fast structural changes under thermal equilibrium conditions. Such transformations are involved in a vast array of chemical problems. Experimentally measuring equilibrium dynamics is a challenging problem that is at the forefront of chemical research. This review describes ultrafast 2D IR vibrational echo chemical exchange experiments and applies them to several types of molecular systems. The formation and dissociation of organic solute-solvent complexes are directly observed. The dissociation times of 13 complexes, ranging from 4 ps to 140 ps, are shown to obey a relationship that depends on the complex's formation enthalpy. The rate of rotational gauche-trans isomerization around a carbon-carbon single bond is determined for a substituted ethane at room temperature in a low viscosity solvent. The results are used to obtain an approximate isomerization rate for ethane. Finally, the time dependence of a well-defined single structural transformation of a protein is measured. | 18,851,709 |
Hypobromous acid and bromamine production by neutrophils and modulation by superoxide. | MPO (myeloperoxidase) catalyses the oxidation of chloride, bromide and thiocyanate to their respective hypohalous acids. We have investigated the generation of HOBr by human neutrophils in the presence of physiological concentrations of chloride and bromide. HOBr was trapped with taurine and detected by monitoring the bromination of 4-HPAA (4-hydroxyphenylacetic acid). With 100 microM bromide and 140 mM chloride, neutrophils generated HOBr and it accounted for approx. 13% of the hypohalous acids they produced. Addition of SOD (superoxide dismutase) doubled the amount of HOBr detected. Therefore we investigated the reaction of superoxide radicals with a range of bromamines and bromamides and found that superoxide radicals stimulated the decomposition of these species, with this occurring in a time- and dose-dependent manner. The protection afforded by SOD against such decay demonstrates that these processes are superoxide-radical-dependent. These data are consistent with neutrophils generating HOBr at sites of infection and inflammation. Both HOBr and bromamines/bromamides have the potential to react with superoxide radicals to form additional radicals that may contribute to inflammatory tissue damage. | 18,851,713 |
The usefulness of contrast during exercise echocardiography for the assessment of systolic pulmonary pressure. | The systolic pulmonary artery pressure (PAPs) can be accurately estimated, non-invasively, using continuous-wave Doppler (CWD) ultrasound measurement of the peak velocity of a tricuspid regurgitant (TR) jet. However, it is often difficult to obtain adequate tricuspid regurgitation signals for measurement of PAPs, what could lead to its underestimation. Therefore, utilization of air-blood-saline contrast has been implemented for the improvement of Doppler signal in several clinical contexts. It is now recommended in the evaluation of patients with pulmonary hypertension. Physical activity is severely restricted in patients with PAH, being exertional dypnea the most typical symptom. Exercise stress echo-Doppler imaging allows assessment of the response to exercise. It is an excellent screening test for patients with suspected PAH. Our purpose was to evaluate the value and accuracy of agitated saline with blood contrast echocardiography, in the improvement of the Doppler signal, to quantify PAPs during treadmill exercise-echocardiography. To evaluate the value of contrast echocardiography, using agitated saline with blood, in the improvement of the Doppler signal used to quantify the pulmonary artery systolic pressure during exercise. From a total of 41 patients (pts), we studied 38 pts (93%), 35 women, aged 54 +/- 12 years-old. 27 with the diagnosis of systemic sclerosis, 10 with history of pulmonary embolism and one patient with a suspected idiopathic PAH, who were referred to the Unity of Heart Failure and Pulmonary Hypertension for screening of PAH. According to the Unity protocol, a transthoracic echocardiogram was made, in left decubitus (LD), with evaluation of right ventricle-right atria gradient (RV/RAg). A peripheral venous access was obtained, with a 3-way stopcock and the patients were placed in orthostatism (O), with a new evaluation of RV/RAg. Exercise echocardiography (EE) was begun, with evaluation of RV/RAg at peak exercise (P) and afterwards agitated saline (8 cc with 1 cc of air and 1 cc of blood) was injected, followed by a new evaluation of RV/RAg (PC) and then the interruption of the EE. Pulmonary Hypertension was diagnosed when RV/RAg at the end of the exercise was superior to 40 mmHg. The quality of Doppler signal was deteriorated in 5 pts, maintained in 6 pts and improved in 26 pts, with the use of contrast. In one patient, an interventricular septal defect was diagnosed. In 6 pts, a Doppler signal was only obtained with the use of contrast. In 15 pts, a RV/RAg superior to 40 mmHg was only obtained with the use of contrast. Of these, 9 have already been submitted to right heart cathetherism, that confirmed the diagnosis of pulmonary hypertension in 5 of them (56%). RV/RAg (P) was 44 +/- 11 mmHg and RV/RAg (PC) was 54 +/- 11 mmHg, p < 0,001. 1. The method is applicable in a large number of patients. 2. RV/RA gradients obtained at peak exercise are higher with the use of contrast, and the clinical meaning of this difference should be evaluated in a larger number of pts submitted to right heart cathetherism. The high number of false positives should lead to a higher diagnostic threshold. 3. This method seems to have relevant clinical value in the diagnosis of pulmonary arterial hypertension. | 18,851,729 |
Transposition of the great arteries. | Transposition of the great arteries (TGA), also referred to as complete transposition, is a congenital cardiac malformation characterised by atrioventricular concordance and ventriculoarterial (VA) discordance. The incidence is estimated at 1 in 3,500-5,000 live births, with a male-to-female ratio 1.5 to 3.2:1. In 50% of cases, the VA discordance is an isolated finding. In 10% of cases, TGA is associated with noncardiac malformations. The association with other cardiac malformations such as ventricular septal defect (VSD) and left ventricular outflow tract obstruction is frequent and dictates timing and clinical presentation, which consists of cyanosis with or without congestive heart failure. The onset and severity depend on anatomical and functional variants that influence the degree of mixing between the two circulations. If no obstructive lesions are present and there is a large VSD, cyanosis may go undetected and only be perceived during episodes of crying or agitation. In these cases, signs of congestive heart failure prevail. The exact aetiology remains unknown. Some associated risk factors (gestational diabetes mellitus, maternal exposure to rodenticides and herbicides, maternal use of antiepileptic drugs) have been postulated. Mutations in growth differentiation factor-1 gene, the thyroid hormone receptor-associated protein-2 gene and the gene encoding the cryptic protein have been shown implicated in discordant VA connections, but they explain only a small minority of TGA cases.The diagnosis is confirmed by echocardiography, which also provides the morphological details required for future surgical management. Prenatal diagnosis by foetal echocardiography is possible and desirable, as it may improve the early neonatal management and reduce morbidity and mortality. Differential diagnosis includes other causes of central neonatal cyanosis. Palliative treatment with prostaglandin E1 and balloon atrial septostomy are usually required soon after birth. Surgical correction is performed at a later stage. Usually, the Jatene arterial switch operation is the procedure of choice. Whenever this operation is not feasible, adequate alternative surgical approach should be implemented. With the advent of newer and improved surgical techniques and post operative intensive care, the long-term survival is approximately 90% at 15 years of age. However, the exercise performance, cognitive function and quality of life may be impaired. | 18,851,735 |
Sample processing for DNA chip array-based analysis of enterohemorrhagic Escherichia coli (EHEC). | Exploitation of DNA-based analyses of microbial pathogens, and especially simultaneous typing of several virulence-related genes in bacteria is becoming an important objective of public health these days. A procedure for sample processing for a confirmative analysis of enterohemorrhagic Escherichia coli (EHEC) on a single colony with DNA chip array was developed and is reported here. The protocol includes application of fragmented genomic DNA from ultrasonicated colonies. The sample processing comprises first 2.5 min of ultrasonic treatment, DNA extraction (2x), and afterwards additional 5 min ultrasonication. Thus, the total sample preparation time for a confirmative analysis of EHEC is nearly 10 min. Additionally, bioinformatic revisions were performed in order to design PCR primers and array probes specific to most conservative regions of the EHEC-associated genes. Six strains with distinct pathogenic properties were selected for this study. At last, the EHEC chip array for a parallel and simultaneous detection of genes etpC-stx1-stx2-eae was designed and examined. This should permit to sense all currently accessible variants of the selected sequences in EHEC types and subtypes. In order to implement the DNA chip array-based analysis for direct EHEC detection the sample processing was established in course of this work. However, this sample preparation mode may also be applied to other types of EHEC DNA-based sensing systems. | 18,851,736 |
Probabilistic base calling of Solexa sequencing data. | Solexa/Illumina short-read ultra-high throughput DNA sequencing technology produces millions of short tags (up to 36 bases) by parallel sequencing-by-synthesis of DNA colonies. The processing and statistical analysis of such high-throughput data poses new challenges; currently a fair proportion of the tags are routinely discarded due to an inability to match them to a reference sequence, thereby reducing the effective throughput of the technology. We propose a novel base calling algorithm using model-based clustering and probability theory to identify ambiguous bases and code them with IUPAC symbols. We also select optimal sub-tags using a score based on information content to remove uncertain bases towards the ends of the reads. We show that the method improves genome coverage and number of usable tags as compared with Solexa's data processing pipeline by an average of 15%. An R package is provided which allows fast and accurate base calling of Solexa's fluorescence intensity files and the production of informative diagnostic plots. | 18,851,737 |
Delayed involution of lactation presenting as a non-resolving breast mass: a case report. | Involution of lactation is a physiological process. Rarely, it may be delayed and troublesome for the lactating woman. Though lactation-induced changes in breast are well known, morphological features of delayed involution are not clear. We report a case of a 22-year-old lactating mother who presented with a painful, non-resolving breast mass 5 months after delivery. Clinically, it simulated an inflammatory carcinoma. Histopathology, however, revealed involuting lactational changes. To the best of our knowledge, lactational involution with such a presentation has not been described in the English literature. The case needs to be reported so that this entity can be considered among the differential diagnoses of breast masses in a lactating patient. | 18,851,738 |
Patterns of hand preference for pairs of actions and the classification of handedness. | Pairs of actions such as write x throw and throw x racquet were examined for items of the Annett hand preference questionnaire (AHPQ). Right (R) and left (L) responses were described for frequencies of RR, RL, LR, and LL pairings (write x throw etc.) in a large representative combined sample with the aim of discovering the distribution over the population as a whole. The frequencies of RL pairings varied significantly over the different item pairs but the frequencies of LR pairings were fairly constant. An important difference was found between primary actions (originally write, throw, racquet, match, toothbrush, hammer with the later addition of scissors for right-handers) and non-primary actions (needle and thread, broom, spade, dealing playing cards, and unscrewing the lid of a jar). For primary actions, there were similar numbers of right and left writers using the 'other' hand. For non-primary actions more right-handers used the left hand than for primary actions but more left-handers did not use the right hand. That is, different frequencies of response to primary versus non-primary actions were found for right-handers but not for left-handers. The pattern of findings was repeated for a corresponding analysis of left-handed throwing x AHPQ actions. The findings have implications for the classification of hand preferences and for analyses of the nature of hand skill. | 18,851,767 |
[Specific antitumor effect of adeno-associated virus vector carrying TRAIL gene under the control of hTERT promoter]. | Adeno-associated virus (AAV) has been widely used in tumor gene therapy. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a safe and potent anti-tumor gene which could induce apoptosis of many tumor cells. This study was to use tumor-specific promoter hTERT to construct AAV-hTERT-TRAIL, and explore its antitumor effect and mechanism in vitro. Purified AAV-hTERT-TRAIL was obtained after co-transfection of HEK293 with pAAV-hTERT-TRAIL and two other help plasmids. After transfection of AAV-hTERT-TRAIL into three tumor cell lines, SW620, HepG2, A549 and two normal cell lines, NHLF and MRC5, the expression of TRAIL was detected by RT-PCR, Western blot and immunohistochemistry (IHC); the influence of AAV-hTERT-TRAIL transfection on cell proliferation was evaluated using MTT assay. Activation of caspase-3 and PARP was measured by Western blot. Cell apoptosis was assessed using ELISA and flow cytometry. AAV-hTERT-TRAIL was successfully packaged in HEK293 cells. After AAV-hTERT-TRAIL infection, specific expression of TRAIL was detected in three tumor cell lines, but not in two normal cell lines. Cell proliferation rates in SW620, A549, HepG2, NHLF and MRC5 cells were 41.55%, 44.29%, 49.95%, 84.59% and 87.22%, respectively after transfection of AAV-hTERT-TRAIL at a multiplicity of infection (MOI) of 100 for 96 h. AAV-hTERT-TRAIL activated caspase-3 apoptotic pathway and induced apoptosis in tumor cell lines, but not in normal cell lines. hTERT increases selectivity and safety of AAV vector. hTERT promoter controls the expression of anti-tumor genes to specifically induce death of tumor cells. | 18,851,780 |
[Inhibitory effect of N-terminal 24 amino acids of the p55 gamma, a regulatory subunit of phosphoinositide 3-kinase, on proliferation of colon carcinoma cell line HT29]. | p55 gamma is one of the regulatory subunits of phosphoinositide 3-kinase (PI3K), which plays an important role in the regulation of PI3K activity. This study was to explore the inhibitory effect of the N-terminal 24 amino acids of the p55 gamma on proliferation of colon carcinoma cell line HT29. Ad-N24p55-GFP, containing N-terminal 24 amino acids of the p55 gamma, and control vector Ad-GFP were constructed, and used to infect HT29 cells. The cell cycle progression was detected using flow cytometry. DNA synthesis was analyzed using the BrdU/PI method. The nude mice model bearing HT29 xenograft tumors was used to study the effect of Ad-N24p55-GFP against the tumor. Compared with cells infected with Ad-GFP, cells infected with Ad-N24p55-GFP at the G0/G1 phase were increased from 65.11% to 73.39% P < 0.05, and cells at S and G2/M phases were decreased from 17.37% to 15.08% and from 17.51% to 11.13%, respectively; BrdU-positive cells were decreased from 24.82% to 9.27%. In the nude mice model, the tumor growth was inhibited after the administration of Ad-N24p55-GFP. The tumor weight was (0.32+/-0.08)g vs. (10.67+/-0.3)g and (0.72+/-0.28)g in the Ad-N24P55-GFP group,the blank control group and the Ad-GFP group, respectively. In HT29 cells, overexpression of the N-terminal 24 amino acids of the p55 gamma can induce cell cycle arrest, inhibit DNA synthesis and inhibit tumor growth in the nude mice model of HT29 xenograft tumors. | 18,851,781 |
Clinical applications of bone morphogenetic proteins: current evidence. | Bone morphogenetic proteins (BMPs) were first described by Dr. Marshall Urist in 1965. Since 1988 a series of clinical studies and randomized clinical trials have evaluated the application of these molecules in humans. A comprehensive review of 30 clinical studies was performed to elicit the existing evidence of the English orthopaedic literature. BMPs appear to be efficacious as the reported success rates are equivalent and perhaps superior to those achieved with the gold standard methods of autografting. Clinical safety assessments have been even more encouraging with just a few reports of adverse events related to their use in clinical practice. There are certain controversies on the presented results of all the reviewed clinical series, which reflect the complexity of the osteoinductive and osteoconductive role of the BMPs, the ongoing quest for optimization of the dosing schemes and delivery carriers, as well as the multifactorial interactions during bone formation and remodeling. | 18,851,797 |
Rate and risk factors for blood transfusion in patients undergoing periacetabular osteotomy. | Periacetabular osteotomy has become the procedure of choice in many centers for the treatment of symptomatic hip dysplasia in young patients without severe secondary hip arthritis. Reorientation pelvic osteotomy has the potential for large blood loss and the need for blood transfusion. Between 1996 and 2003, 108 periacetabular osteotomies (107 patients) were performed by one of the authors. There were 84 females and 23 males with an average age of 30 years at the time of surgery. The overall allograft transfusion rate was 20% (21/108). Ninety-four percent (101/108) of the patients received transfusions including autologous blood, intraoperative cell saver, and postoperative allograft transfusion. The average transfusion amount (cell saver and allograft) was 2.14 units per patient. The risk for transfusion between males and females was not significantly different. The data from this study suggest that the vast majority of patients undergoing periacetabular osteotomy will require some form of transfusion, with 20% requiring allograft blood. The need for allograft blood will be minimal if the preoperative hemoglobin is greater than 12 g/dL. | 18,851,804 |
Late postoperative infection following spinal instrumentation: stainless steel versus titanium implants. | Late postoperative infection following instrumented spinal surgery is a clinical entity that has emerged in recent years. The extended surface of the spinal instrumentation in combination with hematogenous seeding or intraoperative inoculation is the main predisposing factor. In order to investigate the contribution of the instrumentation material (stainless steel versus titanium implants) and mechanical loosening, two groups of patients are presented. The first group includes 50 idiopathic scoliotic patients who were treated with first-generation posterior stainless steel spinal segmental multihook instrumentation [Texas Scottish Rite Hospital (TSRH) instrumentation system], and the second group includes 45 similar patients who were treated with newer titanium implants (MOSS MIAMI, XIA, and CD). Follow-up ranged from 3 to 13 years. Six patients from the first group and one patient from the second group presented with late infections 1 to 7 years postoperatively. Common intraoperative findings were excessive inflammatory tissue and some degree of instrumentation loosening and corrosion (stainless steel). Removal of instrumentation in combination with appropriate antibiotics was an effective treatment. Further study with long-term follow-up is necessary in order to understand the exact incidence and pathology of such infections. | 18,851,806 |
Lateral and medial plantar pressures after split versus whole anterior tibialis tendon transfer. | If whole and split transfer of the anterior tibialis tendon (SPLATT) do not differ in balancing the forefoot, whole tendon transfer would provide a simpler alternative as part of treatment of an equinovarus deformity. We hypothesized that no significant differences in percent plantar lateral forefoot pressures would be observed between split and whole tendon transfer. We used a spastic model to test the hypothesis that overcorrection would not occur with whole tendon transfer. In ten specimens from five lower extremity matched pairs, a SPLATT was anchored to the cuboid. After loading, simulated whole tendon transfer to the lateral cuneiform was done. Normal loading was Achilles, 250 N, tibialis anterior, 200 N, peroneals/tibialis posterior, 142 N; and spastic loading was Achilles, 500 N, tibialis anterior, 400 N, peroneals/tibialis posterior, 142 N. Pressure data were collected for both normal and spastic conditions. Percent of forefoot pressure was calculated for the lateral and medial sector. Percent lateral pressure was slightly lower after whole tendon transfer (normal, p < 0.01; spastic, p < 0.01). This difference was not clinically important. Medial pressure did not differ in the spastic versus the normal model after split or whole tendon transfer. Whole and split anterior tibialis tendon transfer both resulted in a balanced forefoot. Neither whole tendon nor split tendon transfer resulted in overcorrection in a simulated spastic model. Whole tendon transfer may be an effective and simpler alternative to SPLATT for unloading the lateral forefoot in both a normal and a spastic foot. | 18,851,822 |
MLK3 limits activated Galphaq signaling to Rho by binding to p63RhoGEF. | Mixed lineage kinase 3 (MLK3) is a MAP3K that activates the JNK-dependent MAPK pathways. Here, we show that MLK3 is required for cell migration in a manner independent of its role as a MAP3K or MLK3 kinase activity. Rather, MLK3 functions in a regulated way to limit levels of the activated GTPase Rho by binding to the Rho activator, p63RhoGEF/GEFT, which, in turn, prevents its activation by Galphaq. These findings demonstrate a scaffolding role for MLK3 in controlling the extent of Rho activation that modulates cell migration. Moreover, they suggest that MLK3 functions as a network hub that links a number of signaling pathways. | 18,851,832 |
RBM5/Luca-15/H37 regulates Fas alternative splice site pairing after exon definition. | RBM5/Luca-15/H37 is a gene frequently inactivated in lung cancers and overexpressed in breast tumors. Its protein product has been detected in prespliceosomal complexes and modulates cell proliferation and Fas-mediated apoptosis. We report that RBM5 is a component of complexes involved in 3' splice site recognition and regulates alternative splicing of apoptosis-related genes, including the Fas receptor, switching between isoforms with antagonistic functions in programmed cell death. In contrast with classical mechanisms of splicing regulation, RBM5 does not affect early events of splice site recognition that lead to Fas exon 6 definition. Instead, RBM5 inhibits the transition between prespliceosomal complexes assembled around exon 6 to mature spliceosomes assembled on the flanking introns and promotes sequence-specific pairing of the distal splice sites. An OCRE domain important for RBM5 function contacts components of the U4/5/6 tri-snRNP, consistent with the idea that RBM5 modulates splice site pairing after prespliceosome assembly and exon definition. | 18,851,835 |
MyoD targets TAF3/TRF3 to activate myogenin transcription. | Skeletal muscle differentiation requires a cascade of transcriptional events to control the spatial and temporal expression of muscle-specific genes. Until recently, muscle-specific transcription was primarily attributed to prototypic enhancer-binding factors, while the role of core promoter recognition complexes in directing myogenesis remained unknown. Here, we report the development of a purified reconstituted system to analyze the properties of a TAF3/TRF3 complex in directing transcription initiation at the Myogenin promoter. Importantly, this new complex is required to replace the canonical TFIID to recapitulate MyoD-dependent activation of Myogenin. In vitro and cell-based assays identify a domain of TAF3 that mediates coactivator functions targeted by MyoD. Our findings also suggest changes to CRSP/Mediator in terminally differentiated myotubes. This switching of the core promoter recognition complex during myogenesis allows a more balanced division of labor between activators and TAF coactivators, thus providing another strategy to accommodate cell-specific regulation during metazoan development. | 18,851,836 |
An examination of the interactions between mothers and children with anxiety disorders. | This study examined the association between parenting styles and mother and child anxiety. Maternal overinvolvement and negativity/criticism were evaluated during a speech preparation task (N=135 dyads) and a Five Minute Speech Sample (FMSS) from mothers (N=155). During the speech task interaction, mothers of anxious children (aged 4-16 years), regardless of their own anxiety, were observed to be more overinvolved than mothers of nonanxious children. Similarly, the FMSS showed that mothers of anxious children (aged 4-17 years) were more overprotective, self-sacrificing, or nonobjective than mothers of nonanxious children, irrespective of maternal anxiety status. No differences in maternal negativity were found on the speech task between any of the groups. However, the FMSS showed that mothers of anxious children were more critical than mothers of nonanxious children, regardless of maternal anxiety status. These results support the relationship between overinvolved, critical parenting and child anxiety, but suggest that maternal anxiety is not associated with increased overinvolvement or criticism. Theoretical implications are discussed. | 18,851,844 |
Serum progesterone on the day of human chorionic gonadotropin administration predicts clinical pregnancy of sibling frozen embryos. | To evaluate patient characteristics and fresh in vitro fertilization (IVF) cycle parameters that influence success of sibling frozen-thawed embryo transfer (FET) cycles. Retrospective study. Academic infertility practice. Infertile women undergoing FET cycles using embryos cryopreserved on day 3 after insemination after an initial fresh IVF cycle. 90 FET cycles. Clinical pregnancy (CP). The likelihood of CP after FET was statistically significantly higher in women who had achieved CP in the preceding fresh IVF cycle (71.4% vs. 40.6%). Multivariable logistic regression analysis confirmed that patients achieving CP after the fresh IVF cycle were more likely to achieve CP after FET (OR 5.5; 95% CI, 1.2-25.3) after adjusting for age, number, and cleavage status of embryos transferred. Additionally, higher serum levels of progesterone on the day of human chorionic gonadotropin administration emerged as predictive of CP after FET at a statistically significant level. The outcome of the fresh embryo transfer cycle is the foremost predictor of CP after FET of the sibling embryos. The relationship between serum progesterone on the day of human chorionic gonadotropin administration in the fresh cycle and the outcome of subsequent FET is noteworthy and merits further investigation. | 18,851,847 |
Effect of oral N-acetyl cysteine on recurrent preterm labor following treatment for bacterial vaginosis. | To evaluate the effect of N-acetyl cysteine (NAC) on gestational age at delivery in women with previous preterm labor and bacterial vaginosis. A randomized, double-blind, placebo-controlled trial with 280 women between 16 and 18 weeks of pregnancy who had 1 previous preterm birth and had just been successfully treated for bacterial vaginosis with metronidazole for 1 week. The women were randomized to receive 0.6 g of NAC per day plus 17-hydroxyprogesterone caproate (17-OHPC) or placebo plus 17-OHPC until 36 completed weeks of pregnancy or active labor. A vaginal swab was taken during labor. Reaching 36 weeks of pregnancy was more frequent (P<0.05) and gestational age at delivery was significantly higher in the NAC than in the placebo group (37.4 weeks+/-0.4 weeks vs 34.1 weeks+/-1.2 weeks, P<0.05). The discontinuation rate was 11.4% in the NAC group. Oral NAC was found to reduce the recurrence of preterm birth in patients with bacterial vaginosis. | 18,851,855 |
Polybrominated diphenyl ether flame retardants in lichens and mosses from King George Island, maritime Antarctica. | Lichens and mosses are considered good indicators of atmospheric pollution as they absorb contaminants directly from the air. Polybrominated diphenyl ethers (PBDEs) are man-made chemicals used as flame retardants in materials such as plastics, textiles, electronic circuitry and furnishing foam. Few studies have investigated PBDEs in the southern hemisphere including Antarctica. This paper presents the first evaluation of PBDEs in lichens (Usnea antarctica and Usnea aurantiaco-atra) and mosses (Sanionia uncinata) collected at King George Island, maritime Antarctica. PBDEs were detected at low levels in all lichen and moss samples. On average, the levels of PBDEs in mosses (818 pg g(-1) dry weight; 101 ng g(-1) lipid) were significantly higher than in lichens (168 pg g(-1) dry weight; 9.11 ng g(-1) lipid). This difference is most likely due to the differing mechanisms of PBDEs uptake from the atmosphere which are controlled by a number of chemical, environmental and plant variables. Contaminant concentrations were not statistically different at sites close to and distant from human facilities. Long-range atmospheric transport is believed to be the primary source of PBDEs to King George Island. The pattern of congeners in plants resembles those found in commercial mixtures of Penta-BDE. In addition, the presence of BDE-183 in lichens and mosses suggests that other technical formulations (e.g., Octa-BDE and Deca-BDE) have reached Antarctica. Further studies are needed to better understand the role of Antarctic vegetation as a sink for anthropogenic organic pollutants. | 18,851,870 |
The control of dendritic cell maturation by pH-sensitive polyion complex micelles. | Double-hydrophilic block copolymer micelles were designed as vectors for ex vivo dendritic cell engineering to improve the delivery of therapeutic molecules in such immune cells. Polymethacrylic acid-b-polyethylene oxide (PMAA(2100)-b-POE(5000))/poly-L-lysine micelles were optimised and showed a hydrodynamic diameter of 30 nm with a peculiar core organised with hydrogen bonds as well as hydrophobic domains. The micelles proved high stability in physiological conditions (pH and ionic strength) and were also able to disassemble under acidic conditions mimicking acidic endolysosomes. The efficient endocytosis of the optimised micelles tested on bone marrow-derived dendritic cells was monitored by fluorescence-activated cell sorting and microscopy analysis. Finally, the micelle biocompatibility permitted a complete control of the dendritic cell-maturation process widening the therapeutical potential of such engineered dendritic cells for cancer vaccines as well as for immunomodulation in autoimmune diseases. | 18,851,879 |
The performance of docetaxel-loaded solid lipid nanoparticles targeted to hepatocellular carcinoma. | Human hepatocellular carcinoma (HCC) is one of the major causes of death worldwide. Targeted uptake of therapeutic agent in the cell-, tissue- or disease-specific manner represents a potential technology for the treatment of HCC. A new docetaxel-loaded hepatoma-targeted solid lipid nanoparticle (tSLN) was designed and prepared with galactosylated dioleoylphosphatidyl ethanolamine. The cellular cytotoxicity, cellular uptake, subcellular localization, in vivo toxicity, therapeutic effect, biodistribution and histology of tSLNs were investigated. The tSLNs showed the particle size about 120nm with encapsulation efficiency >90%, a low burst effect within the first day and a sustained release for the next 29 days in vitro. Cytotoxicity of tSLNs against hepatocellular carcinoma cell line BEL7402 was superior to Taxotere and non-targeted SLNs (nSLNs). The tSLNs also showed better tolerant and antitumor efficacy in murine model bearing hepatoma compared with Taxotere or nSLNs. The studies on cellular uptake and biodistribution indicated that the better antitumor efficacy of tSLNs was attributed to both the increased accumulation of drug in tumor and more cellular uptake by hepatoma cells. The histology demonstrated that tSLNs had no detrimental effect on both healthy liver and liver with fibrosis. These results implied that this targeted nanocarrier of docetaxel could enhance its antitumor effect in vivo with low systemic toxicity for the treatment of locally advanced and metastatic HCC. | 18,851,881 |
A prospective study of hormonal treatment and anxiety disorders in community-dwelling elderly women (the Esprit Study). | The impact of hormone therapy use on late-life anxiety disorder in elderly women has not been evaluated. Anxiety disorders were evaluated in 838 community-dwelling postmenopausal women aged 65 years and over, randomly recruited from electoral rolls. Anxiety disorders were assessed using a standardized psychiatric examination based on DSM-IV criteria, at baseline and as part of the 2- and 4-year follow-up. Multivariate logistic regression analyses adjusted for socio-demographic variables, measures of physical health and cognitive impairment, as well as current depressive symptomatology indicated no significant association between hormone therapy and anxiety disorders at baseline or after the 4-year follow-up period, regardless of type of treatment. Compared to women who have never taken hormonal therapy, no significant difference was observed for women taking continuously hormone therapy over the follow-up or those who stopped their treatment. The use of hormone therapy was not associated with improved anxiety symptomatology in elderly postmenopausal women. | 18,851,886 |
"So, are you back to work yet?" Re-conceptualizing 'work' and 'return to work' in the context of primary bone cancer. | People with primary bone cancer typically are young (usual age-at-onset 16-35 years old) and undergo arduous treatments. The current standard of care (tumour resection and limb reconstruction with or without chemotherapy) results in survival rates in excess of 60%, but also results in significant disability at a time when patients are choosing career paths, establishing their independence and embarking on new roles. To date, the nature of the relationship between experiences of osteosarcoma illness and experiences of vocation has remained unclear. This study sought to examine this relationship using qualitative narrative methodology. In-depth audiotaped interviews were conducted with 14 osteosarcoma survivors (8 men, 6 women) who were being treated at Mount Sinai Hospital, Toronto, Canada. Interview transcripts were analyzed for story typology and thematic content via constant comparison. Respondents reported engaging in three types of 'work': 'illness work', 'identity work' and 'vocational work'. Osteosarcoma illness represented a crisis for respondents, one which necessitated considerable illness work. Illness work was portrayed as all-consuming, whereby respondents were forced to stop vocational work for considerable periods. The illness crisis also precipitated 'identity work'. Respondents recounted a transformative process, of 'becoming other' to whom they had been prior to illness. As a result, respondents told of re-entering the vocational sphere with a different sense of themselves from when they left it. When patients return for surgical follow up, clinicians routinely ask, "So, are you back to work yet?" expecting simple 'yes/no' answers. This study suggests that the answer is instead highly complex, and that patients could be seen as having been 'working' all along. This study offers a re-conceptualization of 'work' and 'return to work' in the context of osteosarcoma, with implications for clinical and return-to-work practices. | 18,851,893 |
The effect of tianeptine in the prevention of radiation-induced neurocognitive impairment. | Radiation-induced neurocognitive impairment is an undesirable radiation-induced toxicity and a common health problem in patients with primary or metastatic brain tumor. It greatly impairs quality of life for long-term brain tumor survivors. Hippocampus is the most important brain structure for neurocognitive functions. It has been shown that radiation affects the hippocampal neurogenesis due to either induce the apoptosis or reduce the precursor cell proliferation in the hippocampus. Radiation-induced microglial inflammatory response is also negative regulator of neurogenesis. Tianeptine is a clinically effective antidepressant that induces neurogenesis. It has also been shown that tianeptine is able to reduce apoptosis and cytoprotective against the effects of proinflammatory cytokines in the hippocampus. Given the putative role of impaired hippocampal neurogenesis in radiation-induced neurocognitive impairment we think that tianeptine can be effective for preventing radiation-induced neurocognitive impairment by increasing hippocampal neurogenesis. | 18,851,901 |
Tetrakis-azaaromatic quaternary ammonium salts: novel subtype-selective antagonists at neuronal nicotinic receptors that mediate nicotine-evoked dopamine release. | A series of tetrakis-azaaromatic quaternary ammonium salts was synthesized to identify compounds with higher affinity and selectivity as antagonists at neuronal nicotinic receptor subtypes (nAChR) that mediate nicotine-evoked DA release. A high hit rate was achieved in identifying potent analogs that inhibit these nAChRs. Three tetrakis analogs, 11j, 11f, and 11g, were identified as potent (IC(50)=3, 28 and 56nM, respectively) antagonists at these receptors. These compounds represent a novel structural class of nicotinic receptor antagonists. | 18,851,914 |
The first intermediate host of Paragonimus westermani in Sri Lanka. | Freshwater snails (family Paludomidae, genus Paludomus) were collected from streams in Hedeniya and Peradeniya (the campus of Peradeniya University), Kandy district, Central Province, Sri Lanka, and found to harbor rediae and cercariae of a Paragonimus sp. These larvae were identified as Paragonimus westermani by using ITS2 DNA sequences. The infection rates of P. westermani in Paludomus sp. in Hedeniya and Peradeniya were 0.1% (one of 1014) and 0.2% (two of 1006), respectively. The snail has not been identified to species in the present study. This is the first report of the snail host of Paragonimus in Sri Lanka. | 18,851,937 |
ABCB1 and ABCC1 expression in peripheral mononuclear cells is influenced by gene polymorphisms and atorvastatin treatment. | This study investigated the effects of atorvastatin on ABCB1 and ABCC1 mRNA expression on peripheral blood mononuclear cells (PBMC) and their relationship with gene polymorphisms and lowering-cholesterol response. One hundred and thirty-six individuals with hypercholesterolemia were selected and treated with atorvastatin (10 mg/day/4 weeks). Blood samples were collected for serum lipids and apolipoproteins measurements and DNA and RNA extraction. ABCB1 (C3435T and G2677T/A) and ABCC1 (G2012T) gene polymorphisms were identified by polymerase chain reaction-restriction (PCR)-RFLP and mRNA expression was measured in peripheral blood mononuclear cells by singleplex real-time PCR. ABCB1 polymorphisms were associated with risk for coronary artery disease (CAD) (p<0.05). After atorvastatin treatment, both ABCB1 and ABCC1 genes showed 50% reduction of the mRNA expression (p<0.05). Reduction of ABCB1 expression was associated with ABCB1 G2677T/A polymorphism (p=0.039). Basal ABCB1 mRNA in the lower quartile (<0.024) was associated with lower reduction rate of serum low-density lipoprotein (LDL) cholesterol (33.4+/-12.4%) and apolipoprotein B (apoB) (17.0+/-31.3%) when compared with the higher quartile (>0.085: LDL-c=40.3+/-14.3%; apoB=32.5+/-10.7%; p<0.05). ABCB1 substrates or inhibitors did not affect the baseline expression, while ABCB1 inhibitors reversed the effects of atorvastatin on both ABCB1 and ABCC1 transporters. In conclusion, ABCB1 and ABCC1 mRNA levels in PBMC are modulated by atorvastatin and ABCB1 G2677T/A polymorphism and ABCB1 baseline expression is related to differences in serum LDL cholesterol and apoB in response to atorvastatin. | 18,851,956 |
Monitoring the tobacco use epidemic III: The host: data sources and methodological challenges. | This Host paper (III of V) reviews key surveillance and evaluation systems that monitor the characteristics, attitudes and behaviors of tobacco users that are crucial for tobacco control efforts. We summarize and expand on the recommendations from the Host Working Group of the National Tobacco Monitoring, Research and Evaluation Workshop. We also discuss research challenges and make additional recommendations for improving tobacco control surveillance and evaluation. We reviewed 10 major US surveys that collect data on tobacco use. A great deal of data is collected but gaps exist. Data collection on cigars, smokeless tobacco, brand, menthols, and PREPs is sparse and infrequent. Also, a number of factors, including, but not limited to, changes in US population composition, declines in survey response rates, and increases in cell phone use present research challenges that may impact the ongoing utility of these systems. Although the field of tobacco control research is an advanced area of public health, improvements in data systems are necessary to accurately evaluate progress and continue tobacco control gains. A coordinated surveillance and evaluation network would increase efficiency and improve the overall utility, quality and timeliness of the current data systems. | 18,851,990 |
Validation of a virus neutralization potency test in BHK-21 cells for rabies immunoglobulins in a two-center study. | A rabies virus neutralization potency test (VNPT), adapted to microplates from the rapid fluorescent focus inhibition test (RFFIT) for rabies therapeutic immunoglobulin potency evaluation, was standardized and validated in a two-center study in Brazil. The two institutes involved in the study were: Instituto Nacional de Controle de Qualidade em Saúde (Fundação Oswaldo Cruz) and Instituto Butantan. Two equine rabies immunoglobulin samples, all diluted to 1IU/ml, were tested against the WHO 2nd Rabies Human Ig International Standard. Four dilutions of the samples and standards were tested with the VNPT. The potency of the samples was calculated in IU/ml using the probit method; linearity, accuracy, repeatability (intra-assay variation), intermediate precision (inter-assay variation) and reproducibility (inter-laboratory variation) were assessed to evaluate the reliability of the VNPT. Laboratories were arbitrarily coded as Laboratory A and Laboratory B. The following results were obtained with the International Standard: (a) linearity, the overall coefficient of correlation of the dose-response curve was -0.97; (b) accuracy, % error of -0.70 (IU/ml); (c) repeatability, 17.06% (Laboratory A) and 11.61% (Laboratory B); (d) intermediate precision, 16.99% (Laboratory A) and 22.05% (Laboratory B); (e) reproducibility, 14.5%. The final conclusion was that VNPT presents satisfactory linearity, accuracy, repeatability, intermediate precision and reproducibility and is a reliable and suitable method by which to evaluate rabies immunoglobulin potency. | 18,851,992 |
Biofilm production, a marker of pathogenic potential of colonizing and commensal staphylococci. | Biofilm is one of the known virulence factors of staphylococci, a human and animal pathogen and commensal. Some of the strains become invasive under favorable conditions while others do not cause disease. Early detection and management of potentially pathogenic staphylococci is the essential step to prevent device-associated infections. There is also a need to evaluate one simple method for the detection of potential pathogens. Hence this study was planned to study the difference in potential of commensal, colonizing and invasive strains of staphylococci to produce biofilm. We used one qualitative (Congo red agar) and one quantitative (microtiter plate) method for detection of biofilm production and evaluated the sensitivity and specificity of Congo red agar method by using microtiter plate method as a gold standard. We consecutively enrolled staphylococcal strains isolated from peripheral intravenous device (IVD), venous blood, site of IVD insertion and nasal mucosa of patients admitted to pediatric ward with peripheral intravenous devices in place for more than 48 h. Total 100 invasive, 50 colonizing and 50 commensal isolates were studied. Of 100 invasive isolates 74% (74/100) were biofilm positive while only 68% (34/50) colonizing and 32% (16/50) commensal isolates were biofilm positive. The difference in biofilm production by commensal, colonizing and invasive strains was statistically significant (p<0.0001). Sensitivity and specificity of Congo red agar test for detection of biofilm producers were 90.63% and 90.79% for Staphylococcus aureus and 75.86% and 96.88% respectively for coagulase negative staphylococci. CRA is a method that could be used to determine whether an isolate has the potential for biofilm production or not. | 18,851,996 |
Differences of humoral and cellular immune response to an acellular pertussis booster in adolescents with a whole cell or acellular primary vaccination. | To study the pertussis-specific immune response of adolescents with different prevaccination schedules, we measured the humoral and cell-mediated immunity (CMI) to pertussis antigens before and after a five-component Tdap booster vaccination in 78 adolescents, who had previously received either five doses of a two-component acellular pertussis vaccine (aP; last dose age 4-6 years), four doses of aP (last dose age 18-24 months), or four doses of whole cell pertussis vaccine (wcP; last dose age 18-24 months). The proportion of participants with a twofold rise in titre was 79% against pertussis toxin (PT), 94% against filamentous hemagglutinin (FHA), and 99% against pertactin (PRN) without significant differences between the three groups. However, participants with primary wcP vaccination showed higher postvaccination titres to pertussis toxin (geometric mean titre, GMT 50.3EU/ml) than those with either four (GMT 17.1EU/ml) or five (GMT 16.4EU/ml) previous aP doses. CMI indices to PT, FHA, PRN and fimbriae (FIM) increased after vaccination and were similar between groups. The current adolescent Tdap booster immunization induced good humoral and cellular immune response to pertussis. The higher antibody titres to pertussis toxin may indicate a more effective priming of B cell memory after primary whole-cell vaccination. | 18,852,002 |
Effects of o-aminoazotoluene on liver regeneration and p53 activation in mice susceptible and resistant to hepatocarcinogenesis. | The susceptibility to hepatocellular carcinoma (HCC) varies greatly within human populations in response to environmental risk agents. The mechanisms underlying differential susceptibility are still largely unknown and need to be clarified to improve HCC chemoprevention and therapeutic treatment. Inbred rodent strains with established predispositions for hepatocarcinogenesis offer the opportunity to identify intrinsic susceptibility and resistance factors. Previously, we have characterized mouse strains showing differential susceptibility to o-aminoazotoluene (OAT) and established that susceptibility does not result from OAT metabolism or genotoxicity in the livers of resistant and susceptible mice. In this study we have found that OAT differently affects hepatocyte proliferation in mice after partial hepatectomy (PH). OAT inhibited hepatocyte proliferation by 60-80% in the livers of susceptible mice, whereas resistant mice showed less than 15% inhibition. The inhibition resulted in significant delay of hepatic mass recovery in susceptible mice. OAT induced p53 stabilization and transcriptional activation in response to carcinogen treatment to the same degree in both, susceptible and resistant mice. Taken together, our data support inhibition of hepatocyte proliferation as a major cause for increased mouse susceptibility to hepatocarcinogenesis, and acceleration of functional liver recovery may offer a way to increase resistance to hepatic neoplasms. These results may have relevance to clinical observations of HCCs and implications for HCC chemoprevention and treatment. | 18,852,010 |
The fruit essential oil of Pimpinella anisum L. (Umblliferae) induces neuronal hyperexcitability in snail partly through attenuation of after-hyperpolarization. | Many biological actions of Pimpinella anisum L. (Ainse), including antiepileptic activity have been demonstrated; however, there is no data concerning its precise cellular mechanisms of action. We determined whether the fruit essential oil of anise affect the bioelectrical activity of snail neurons in control condition or after pentylenetetrazol (PTZ) induced epileptic activity. Intracellular recordings were made under the current clamp condition and the effects of anise oil (0.01% or 0.05%) alone or in combination with PTZ were assessed on the firing pattern, action potential configuration and postspike potentials. Anise oil changed the firing pattern from regular tonic discharge to irregular and then to bursting in intact cells or resulted in the robustness of the burst firing and the steepness of the paroxysmal shift induced by PTZ treatment. It also significantly increased the firing frequency and decreased both the after-hyperpolarization potential (AHP) following single action potential and the post-pulse AHP. Likely candidate cellular mechanisms underlying the hyperexcitability produced by anise oil include enhancement of Ca(2+) channels activity or inhibition of voltage and/or Ca(2+) dependent K(+) channels activity underlying AHPs. These finding indicates that a certain caution is needed when Pimpinella anisum is used for treating patients suffering from epilepsy. | 18,852,037 |
Evaluation of anti-inflammatory and antinociceptive activities of some Onosma L. species growing in Turkey. | Roots of Onosma species are used for the treatment of various disorders such as bronchitis, tonsillitis, hemorrhoids as well as alleviating pains in folk medicine in Turkey. The chloroform and ethanol (70%) extracts obtained from the roots of Onosma species (Boraginaceae) growing in Turkey, Onosma aucheranum DC., Onosma isauricum Boiss. and Heldr. (endemic), Onosma sericeum Willd., Onosma tauricum Pallas ex Willd. var. brevifolium DC. (endemic) and Onosma tauricum Pallas ex Willd. var. tauricum (Syn: Onosma velenovskyi Davidov) were evaluated for in vivo anti-inflammatory and antinociceptive activities. For the preliminary screening, carrageenan-induced hind paw edema for the anti-inflammatory activity and, p-benzoquinone-induced abdominal constriction test for the antinociceptive activity were used in mice. The chloroform extracts from Onosma aucheranum and Onosma isauricum and ethanolic extracts from Onosma isauricum and Onosma sericeum demonstrated 28.0%, 34.3%, 24.6% and, 27.5% inhibition in p-benzoquinone-induced abdominal constriction test. The chloroform and ethanol (70%) extracts of Onosma isauricum and ethanol (70%) extract of Onosma sericeum also exhibited marked inhibition, ranging between 12.3-27.3%, 10.5-25.3%, 8.2-22.6%, respectively, in carrageenan-induced hind paw edema model at 100mg/kg dose without gastric damage and the activity was quite comparable to indomethacin (32.0-38.4% inhibition) as a reference sample. Neither death nor gastric bleeding was observed for any of the plant extracts during the acute toxicity evaluation. The experimental data demonstrated that Onosma aucheranum, Onosma isauricum and Onosma sericeum displayed remarkable anti-inflammatory and antinociceptive activities. | 18,852,039 |
Insular cortex representation of dynamic mechanical allodynia in trigeminal neuropathic rats. | Dynamic mechanical allodynia is a widespread symptom of neuropathic pain for which mechanisms are still poorly understood. The present study investigated the organization of dynamic mechanical allodynia processing in the rat insular cortex after chronic constriction injury to the infraorbital nerve (IoN-CCI). Two weeks after unilateral IoN-CCI, rats showed a dramatic bilateral trigeminal dynamic mechanical allodynia. Light, moving stroking of the infraorbital skin resulted in strong, bilateral upregulation of extracellular-signal regulated kinase phosphorylation (pERK-1/2) in the insular cortex of IoN-CCI animals but not sham rats, in whose levels were similar to those of unstimulated IoN-CCI rats. pERK-1/2 was located in neuronal cells only. Stimulus-evoked pERK-1/2 immunopositive cell bodies displayed rostrocaudal gradient and layer selective distribution in the insula, being predominant in the rostral insula and in layers II-III of the dysgranular and to a lesser extent, of the agranular insular cortex. In layers II-III of the rostral dysgranular insular cortex, intense pERK also extended into distal dendrites, up to layer I. These results demonstrate that trigeminal nerve injury induces a significant alteration in the insular cortex processing of tactile stimuli and suggest that ERK phosphorylation contributes to the mechanisms underlying abnormal pain perception under this condition. | 18,852,047 |
Functional and structural synergy for resolution recovery and partial volume correction in brain PET. | Positron Emission Tomography (PET) has the unique capability of measuring brain function but its clinical potential is affected by low resolution and lack of morphological detail. Here we propose and evaluate a wavelet synergistic approach that combines functional and structural information from a number of sources (CT, MRI and anatomical probabilistic atlases) for the accurate quantitative recovery of radioactivity concentration in PET images. When the method is combined with anatomical probabilistic atlases, the outcome is a functional volume corrected for partial volume effects. The proposed method is based on the multiresolution property of the wavelet transform. First, the target PET image and the corresponding anatomical image (CT/MRI/atlas-based segmented MRI) are decomposed into several resolution elements. Secondly, high-resolution components of the PET image are replaced, in part, with those of the anatomical image after appropriate scaling. The amount of structural input is weighted by the relative high frequency signal content of the two modalities. The method was validated on a digital Zubal phantom and clinical data to evaluate its quantitative potential. Simulation studies showed the expected relationship between functional recovery and the amount of correct structural detail provided, with perfect recovery achieved when true images were used as anatomical reference. The use of T1-MRI images brought significant improvements in PET image resolution. However improvements were maximized when atlas-based segmented images as anatomical references were used; these results were replicated in clinical data sets. The synergistic use of functional and structural data, and the incorporation of anatomical probabilistic information in particular, generates morphologically corrected PET images of exquisite quality. | 18,852,055 |
Increased spermine oxidase (SMO) activity as a novel differentiation marker of myogenic C2C12 cells. | Spermine oxidase (SMO) is a FAD-containing enzyme involved in animal cell polyamines (PA) homeostasis, selectively active on spermine and producing H(2)O(2), spermidine, and the 3-aminopropanal. In the present study, we have examined the SMO gene expression during the mouse myoblast C2C12 cell differentiation induced with two different stimuli by RT-PCR analysis, polysome-mRNP distribution and enzyme activity. SMO transcript accumulation and enzymatic activity increases during C2C12 cell differentiation and correlates with the decrease of spermine content. Many proteins are highly regulated during the phenotypic conversion of rapidly dividing C2C12 myoblasts into fully differentiated post-mitotic myotubes. The SMO gene induction represents a novel and additional marker of C2C12 cell differentiation. The sub-cellular localization of the SMOalpha and SMOmu splice variants is not involved in the differentiation processes. Nuclear localization of only the SMOmu protein was confirmed. | 18,852,063 |
Chromosome aberrations in mouse embryos and fetuses produced by assisted reproductive technology. | The occurrence of structural chromosome aberrations in mouse one-cell embryos produced by intracytoplasmic sperm injection (ICSI) with mature spermatozoa was dependent on the type of sperm incubation medium and sperm incubation time. When cauda epididymal spermatozoa were used following incubation in bicarbonate-buffered TYH medium for 0h (no incubation) and 0.5h, the chromosome aberration rates (6.9% and 7.4%, respectively) in the resultant embryos were significantly higher than that (2.3%) in the IVF embryos. However, when the spermatozoa were incubated for 2-2.5h and 6h in the same medium, the chromosome aberration rates were reduced to the IVF embryo level (3.8% and 4.3%, respectively). When spermatozoa incubated in Hepes-buffered H-mCZB and phosphate-buffered PB1 media were used for ICSI, chromosome aberration rates in embryos were significantly high (8.6-28.1%) and increased in a time-dependent manner. On the other hand, when immature testicular spermatozoa were incubated in those three media for 0.5h and 6h, the incidences of resultant embryos with structural chromosome aberrations ranged between 7.4% and 11.7%, and there was no medium- and time-dependent change in these aberration rates. To evaluate transmissible risk of chromosome aberrations to offspring, two- or four-cell embryos derived from cauda epididymal spermatozoa were transferred into the oviducts of pseudopregnant females and chromosomes of live fetuses were examined on gestational day 16. One (2.0%) mosaic fetus was found when spermatozoa were incubated in TYH for 2-2.5h, and there were four (6.7%) fetuses displaying a structurally abnormal karyotype when spermatozoa were incubated in H-mCZB for 2-2.5h, indicating that structural chromosome aberrations generated in ICSI one-cell embryos are transmissible to offspring. The causal mechanism of structural chromosome aberrations in ICSI one-cell embryos is discussed in relation to the acrosomal plasma membrane cholesterol and the acrosome. | 18,852,067 |
Small liver lesions in oncologic patients: characterization with CT, MRI and contrast-enhanced US. | Focal liver lesions (FLLs) are frequently discovered during ultrasound examinations either in healthy subjects without a clinical history of cancer or during staging or follow-up procedures in oncologic patients or in routine surveillance of hepatopathic patients. In oncologic patients, the liver is the most common target of metastatic disease and accurate detection and characterisation of FLLs is prognostically fundamental during the initial staging as well as before and after pre-operative chemotherapy, as it can help to identify patients who are most likely to benefit from liver surgery. Moreover, early detection of primary or secondary liver malignancies increases the possibility of curative surgical resection or successful percutaneous ablation. As many FLLs in these patients are benign, a precise and preferably non-invasive method of differentiation from malignant metastatic nodules is needed. Moreover, the continuous follow-up of cancer patients requires an easily available, reliable and cost-effective diagnostic tool for the detection and characterization of FLLs. | 18,852,087 |
Surface temperatures of the Mid-Pliocene North Atlantic Ocean: implications for future climate. | The Mid-Pliocene is the most recent interval in the Earth's history to have experienced warming of the magnitude predicted for the second half of the twenty-first century and is, therefore, a possible analogue for future climate conditions. With continents basically in their current positions and atmospheric CO2 similar to early twenty-first century values, the cause of Mid-Pliocene warmth remains elusive. Understanding the behaviour of the North Atlantic Ocean during the Mid-Pliocene is integral to evaluating future climate scenarios owing to its role in deep water formation and its sensitivity to climate change. Under the framework of the Pliocene Research, Interpretation and Synoptic Mapping (PRISM) sea surface reconstruction, we synthesize Mid-Pliocene North Atlantic studies by PRISM members and others, describing each region of the North Atlantic in terms of palaeoceanography. We then relate Mid-Pliocene sea surface conditions to expectations of future warming. The results of the data and climate model comparisons suggest that the North Atlantic is more sensitive to climate change than is suggested by climate model simulations, raising the concern that estimates of future climate change are conservative. | 18,852,090 |
Modelling heterotachy in phylogenetic inference by reversible-jump Markov chain Monte Carlo. | The rate at which a given site in a gene sequence alignment evolves over time may vary. This phenomenon--known as heterotachy--can bias or distort phylogenetic trees inferred from models of sequence evolution that assume rates of evolution are constant. Here, we describe a phylogenetic mixture model designed to accommodate heterotachy. The method sums the likelihood of the data at each site over more than one set of branch lengths on the same tree topology. A branch-length set that is best for one site may differ from the branch-length set that is best for some other site, thereby allowing different sites to have different rates of change throughout the tree. Because rate variation may not be present in all branches, we use a reversible-jump Markov chain Monte Carlo algorithm to identify those branches in which reliable amounts of heterotachy occur. We implement the method in combination with our 'pattern-heterogeneity' mixture model, applying it to simulated data and five published datasets. We find that complex evolutionary signals of heterotachy are routinely present over and above variation in the rate or pattern of evolution across sites, that the reversible-jump method requires far fewer parameters than conventional mixture models to describe it, and serves to identify the regions of the tree in which heterotachy is most pronounced. The reversible-jump procedure also removes the need for a posteriori tests of 'significance' such as the Akaike or Bayesian information criterion tests, or Bayes factors. Heterotachy has important consequences for the correct reconstruction of phylogenies as well as for tests of hypotheses that rely on accurate branch-length information. These include molecular clocks, analyses of tempo and mode of evolution, comparative studies and ancestral state reconstruction. The model is available from the authors' website, and can be used for the analysis of both nucleotide and morphological data. | 18,852,097 |
Evaluating the robustness of phylogenetic methods to among-site variability in substitution processes. | Computer simulations provide a flexible method for assessing the power and robustness of phylogenetic inference methods. Unfortunately, simulated data are often obviously atypical of data encountered in studies of molecular evolution. Unrealistic simulations can lead to conclusions that are irrelevant to real-data analyses or can provide a biased view of which methods perform well. Here, we present a software tool designed to generate data under a complex codon model that allows each residue in the protein sequence to have a different set of equilibrium amino acid frequencies. The software can obtain maximum-likelihood estimates of the parameters of the Halpern and Bruno model from empirical data and a fixed tree; given an arbitrary tree and a fixed set of parameters, the software can then simulate artificial datasets.We present the results of a simulation experiment using randomly generated tree shapes and substitution parameters estimated from 1610 mammalian cytochrome b sequences.We tested tree inference at the amino acid, nucleotide and codon levels and under parsimony, maximum-likelihood, Bayesian and distance criteria (for a total of more than 650 analyses on each dataset). Based on these simulations, nucleotide-level analyses seem to be more accurate than amino acid and codon analyses. The performance of distance-based phylogenetic methods appears to be quite sensitive to the choice of model and the form of rate heterogeneity used. Further studies are needed to assess the generality of these conclusions. For example, fitting parameters of the Halpern Bruno model to sequences from other genes will reveal the extent to which our conclusions were influenced by the choice of cytochrome b. Incorporating codon bias and more sources heterogeneity into the simulator will be crucial to determining whether the current results are caused by a bias in the current simulation study in favour of nucleotide analyses. | 18,852,108 |
Class I beta-tubulin mutations in 2-methoxyestradiol-resistant acute lymphoblastic leukemia cells: implications for drug-target interactions. | 2-Methoxyestradiol (2ME2) is a naturally occurring derivative of estradiol that has been shown to be an active small molecule that has antitumor and antiangiogenic properties. 2ME2 binds to beta-tubulin near the colchicine-binding site, inhibits microtubule polymerization, and induces mitotic arrest. To improve understanding of the mechanisms of action and resistance to 2ME2, we selected leukemia cells, CCRF-CEM, that display increasing resistance to 2ME2, and three of the highly resistant sublines were chosen for detailed analysis. The 2ME2 cells selected in 7.2 to 28.8 micromol/L were found to be 47- to 107-fold resistant to 2ME2 and exhibited low levels of cross-resistance to vinblastine. Two of the lowest 2ME2-resistant sublines were significantly hypersensitive to colchicine and epothilone B, but the hypersensitive effects were lost in the highest 2ME2-resistant subline. Moreover, 2ME2-resistant cells require 10-fold higher concentrations of 2ME2 to induce G(2)-M cell cycle arrest and have higher amounts of tubulin polymer compared with parental cells. Gene and protein sequencing revealed four class I beta-tubulin mutations, S25N, D197N, A248T, and K350N, in the 2ME2-resistant cells. The S25N mutation is within the paclitaxel-binding site, whereas A248T and K350N are within the colchicine-binding site on beta-tubulin, yet the resistant cells were not cross-resistant to paclitaxel or colchicine. This strongly suggests that the mutations have induced conformational changes to the binding site that resulted in 2ME2 resistance. The 2ME2-resistant leukemia cells provide novel insights into microtubule stability and drug-target interactions. | 18,852,118 |
Genistein down-regulates androgen receptor by modulating HDAC6-Hsp90 chaperone function. | Androgen receptor (AR) is a ligand-activated transcription factor belonging to the steroid hormone receptor family and is very important for the development and progression of prostate cancer. The soy isoflavone genistein has been shown previously to down-regulate AR in androgen-dependent prostate cancer cell lines such as LNCaP. However, the mechanism(s) by which AR is down-regulated by genistein is still not known fully. We show a new mechanism by which genistein inhibits AR protein levels. We show that genistein-treated LNCaP cells exhibit increased ubiquitination of AR, suggesting that AR protein is down-regulated via a proteasome-mediated pathway. AR is normally stabilized by the chaperone activity of the heat shock protein Hsp90. The increased ubiquitination of AR after genistein treatment is attributed to decreased Hsp90 chaperone activity as assessed by its increased functionally inactive acetylated form. Consistent with this result, we find that HDAC6, which is a Hsp90 deacetylase, is inhibited by the antiestrogenic activity of genistein. Hence, in this study, we elucidate a novel mechanism of AR down-regulation by genistein through inhibition of HDAC6-Hsp90 cochaperone function required to stabilize AR protein. Our results suggest that genistein could be used as a potential chemopreventive agent for prostate cancers along with known inhibitors of HDAC6 and Hsp90. | 18,852,123 |
Human epidermal growth factor receptor (HER-1:HER-3) Fc-mediated heterodimer has broad antiproliferative activity in vitro and in human tumor xenografts. | All four members of the human epidermal growth factor (EGF) receptor (HER) family are implicated in human cancers. Although efficacious in a subset of patients, resistance to single-targeted anti-HER therapy [i.e., cetuximab (Erbitux) and trastuzumab (Herceptin)] is often associated with coexpression of other HER family members. This may be overcome by a HER ligand binding molecule that sequesters multiple EGF-like ligands, preventing ligand-dependent receptor activation. Toward this end, we have combined the HER-1/EGFR and HER-3 ligand binding domains, dimerized with fusion of an Fc fragment of human IgG1. This resulted in a mixture of HER-1/Fc homodimer (HFD100), HER-3/Fc homodimer (HFD300), and HER-1/Fc:HER-3/Fc heterodimer (RB200), also termed Hermodulins. The purified first-generation RB200 bound EGF and neuregulin 1 (NRG1)-beta1 ligands, determined by cross-linking and direct binding studies. The binding affinity for both was approximately 10 nmol/L by dissociation-enhanced lanthanide fluorescence immunoassay using europium (Eu)-labeled ligands. Competition studies with RB200 using Eu-EGF or Eu-NRG1-beta1 revealed that RB200 bound HER-1 ligands, including transforming growth factor-alpha and heparin-binding EGF, and HER-3 ligands NRG1-alpha and NRG1-beta3. RB200 inhibited EGF- and NRG1-beta1-stimulated tyrosine phosphorylation of HER family proteins, proliferation of a diverse range of tumor cells in monolayer cell growth assays, tumor cell proliferation as a single agent and in synergy with tyrosine kinase inhibitors, lysophosphatidic acid-stimulated cell proliferation, and tumor growth in two human tumor xenograft nude mouse models. Taken together, the data reveal that RB200 has the potential to sequester multiple HER ligands and interfere with signaling by HER-1, HER-2, and HER-3. | 18,852,126 |
Coronarin D, a labdane diterpene, inhibits both constitutive and inducible nuclear factor-kappa B pathway activation, leading to potentiation of apoptosis, inhibition of invasion, and suppression of osteoclastogenesis. | Compounds isolated from members of the Zingiberaceae family are traditionally used as a medicine against inflammatory diseases, but little is known about the mechanism. Here, we report the isolation and structural identification of coronarin D [E-labda-8(17),12-diene-15-ol], a labdane-type diterpene, from Hedychium coronarium and delineate its mechanism of action. Because the transcription factor nuclear factor-kappaB (NF-kappaB) is a key mediator of inflammation, apoptosis, invasion, and osteoclastogenesis, we investigated the effect of coronarin D on NF-kappaB activation pathway, NF-kappaB-regulated gene products, and NF-kappaB-regulated cellular responses. The coronarin D inhibited NF-kappaB activation induced by different inflammatory stimuli and carcinogens. This labdane also suppressed constitutive NF-kappaB activity in different cell lines and inhibited IkappaBalpha kinase activation, thus leading to the suppression of IkappaBalpha phosphorylation, degradation, p65 nuclear translocation, and reporter gene transcription. Coronarin D also inhibited the NF-kappaB-regulated gene products involved in cell survival (inhibitor of apoptosis protein 1, Bcl-2, survivin, and tumor necrosis factor receptor-associated factor-2), proliferation (c-myc, cyclin D1, and cyclooxygenase-2), invasion (matrix metalloproteinase-9), and angiogenesis (vascular endothelial growth factor). Suppression of these gene products by the diterpene enhanced apoptosis induced by TNF and chemotherapeutic agents, suppressed TNF-induced cellular invasion, and abrogated receptor activator of NF-kappaB ligand-induced osteoclastogenesis. Coronarin D was found to be more potent than its analogue coronarin D acid. Overall, our results show that coronarin D inhibited NF-kappaB activation pathway, which leads to inhibition of inflammation, invasion, and osteoclastogenesis, as well as potentiation of apoptosis. | 18,852,134 |
Fibroblast growth factor receptor-mediated signals contribute to the malignant phenotype of non-small cell lung cancer cells: therapeutic implications and synergism with epidermal growth factor receptor inhibition. | Fibroblast growth factors (FGF) and their high-affinity receptors (FGFR) represent an extensive cellular growth and survival system. Aim of this study was to evaluate the contribution of FGF/FGFR-mediated signals to the malignant growth of non-small cell lung cancer (NSCLC) and to assess their potential as targets for therapeutic interventions. Multiple FGFR mRNA splice variants were coexpressed in NSCLC cells (n = 16) with predominance of FGFR1. Accordingly, both expression of a dominant-negative FGFR1 (dnFGFR1) IIIc-green fluorescent protein fusion protein and application of FGFR small-molecule inhibitors (SU5402 and PD166866) significantly reduced growth, survival, clonogenicity, and migratory potential of the majority of NSCLC cell lines. Moreover, dnFGFR1 expression completely blocked or at least significantly attenuated s.c. tumor formation of NSCLC cells in severe combined immunodeficient mice. Xenograft tumors expressing dnFGFR1 exhibited significantly reduced size and mitosis rate, enhanced cell death, and decreased tissue invasion. When FGFR inhibitors were combined with chemotherapy, antagonistic to synergistic in vitro anticancer activities were obtained depending on the application schedule. In contrast, simultaneous blockage of FGFR- and epidermal growth factor receptor-mediated signals exerted synergistic effects. In summary, FGFR-mediated signals in cooperation with those transmitted by epidermal growth factor receptor are involved in growth and survival of human NSCLC cells and should be considered as targets for combined therapeutic approaches. | 18,852,144 |
Accounting for ancestry: population substructure and genome-wide association studies. | Accounting for the genetic substructure of human populations has become a major practical issue for studying complex genetic disorders. Allele frequency differences among ethnic groups and subgroups and admixture between different ethnic groups can result in frequent false-positive results or reduced power in genetic studies. Here, we review the problems and progress in defining population differences and the application of statistical methods to improve association studies. It is now possible to take into account the confounding effects of population stratification using thousands of unselected genome-wide single-nucleotide polymorphisms or, alternatively, selected panels of ancestry informative markers. These methods do not require any demographic information and therefore can be widely applied to genotypes available from multiple sources. We further suggest that it will be important to explore results in homogeneous population subsets as we seek to define the extent to which genomic variation influences complex phenotypes. | 18,852,203 |
Genome-based prediction of common diseases: advances and prospects. | Common diseases such as type 2 diabetes and coronary heart disease result from a complex interplay of genetic and environmental factors. Recent developments in genomics research have boosted progress in the discovery of susceptibility genes and fueled expectations about opportunities of genetic profiling for personalizing medicine. Personalized medicine requires a test that fairly accurately predicts disease risk, particularly when interventions are invasive, expensive or have major side effects. Recent studies on the prediction of common diseases based on multiple genetic variants alone or in addition to traditional disease risk factors showed limited predictive value so far, but all have investigated only a limited number of susceptibility variants. New gene discoveries from genome-wide association studies will certainly further improve the prediction of common diseases, but the question is whether this improvement is sufficient to enable personalized medicine. In this paper, we argue that new gene discoveries may not evidently improve the prediction of common diseases to a degree that it will change the management of individuals at increased risk. Substantial improvements may only be expected if we manage to understand the complete causal mechanisms of common diseases to a similar extent as we understand those of monogenic disorders. Genomics research will contribute to this understanding, but it is likely that the complexity of complex diseases may ultimately limit the opportunities for accurate prediction of disease in asymptomatic individuals as unraveling their complete causal pathways may be impossible. | 18,852,206 |
Patients with familial and sporadic onset SLE have similar clinical profiles but vary profoundly by race. | Few large, multi-ethnic studies have examined the clinical and serologic differences between familial and sporadic SLE patients. Understanding these similarities and differences is critical for interpreting genetic studies and developing therapeutic strategies. We compiled information on 1915 patients with SLE in a large multi-racial cohort, including general demographics, pedigree structure and the specific American College of Rheumatology (ACR) criteria met. One patient was randomly selected from each multiplex family for analysis, yielding 554 European-Americans (EA), 373 African-Americans (AA), 193 Hispanics (HI) and 237 patients of other of mixed races. When comparing familial and sporadic patients stratified by race, lupus erythematosus (LE) cells and arthritis were increased in white familial cases (P = 5.5 x 10(-6) and P = 0.028, respectively), but no other significant differences between familial and sporadic patients were found. We found that there were profound differences in clinical profiles between races. For example, photosensitivity and malar rash were decreased in AA (P = 1.3 x 10(-13) and 1.4 x 10(-7), respectively), whereas discoid rash was increased in AA (P = 5.5x10(-6)). EA had significantly less renal disease (P = 5.4x10(-13)), proteinuria (P = 4 x 10(-12)) and anti-Sm (P = 1.7 x 10(-12)) than AA or HI. We, therefore, conclude that familial and sporadic onset patients may be treated similarly with respect to clinical and genetic studies. | 18,852,224 |
Changes in body composition after glucocorticoid therapy in patients with systemic lupus erythematosus. | The aim of this study was to evaluate the changes in body composition after glucocorticoid treatment in patients with systemic lupus erythematosus (SLE). Consecutive SLE patients were recruited for serial measurements (baseline, months 2 and 6) of bone mineral density (BMD) and body composition [bone mineral content (BMC), fat and lean mass] by dual energy X-ray absorptiometry scan after high-dose oral glucocorticoid therapy. Factors correlated with changes in body composition were evaluated. 29 SLE patients were studied (age 39.7 +/- 11.5 years; 83% women with 29% postmenopausal; SLE duration 80.1 +/- 80 months). Fourteen patients (48%) were glucocorticoid-naive. The mean maximum daily dosage of prednisolone was 32.9 +/- 6.5 mg and the cumulative prednisolone dosage in 6 months was 2.7 +/- 0.7 g. At 6 months, a significant drop in BMC of the trunk (-5.0 +/- 2.2%; P = 0.04) and whole body (-1.2 +/- 0.4%; P = 0.002) compared with baseline was observed, and so was the BMD of the hip (-1.7 +/- 0.6%; P = 0.006) and whole body (-0.7 +/- 0.3%; P = 0.01). A significant increase in the fat mass of the trunk (+14.5 +/- 4.1%; P = 0.001) and limbs (+10.0 +/- 3.2%; P = 0.004), but a non-significant drop in lean mass of the trunk (-3.3 +/- 1.8%; P = 0.08) and limbs (-0.8 +/- 2.4%; P = 0.75) also occurred. The changes in whole body BMC correlated significantly with age (rho = -0.51; P = 0.02) and changes in total fat mass (rho = 0.44; P = 0.02) but not with lean mass (rho = -0.21; P = 0.27), gender, body mass index, smoking, prednisolone dosages or changes in BMD. In SLE patients, high-dose glucocorticoids lead to an early and rapid drop in bone mass, which is more serious in older patients and correlates with an increase in body fat. | 18,852,226 |
Staphylococcus aureus elicits marked alterations in the airway proteome during early pneumonia. | Pneumonia caused by Staphylococcus aureus is a growing concern in the health care community. We hypothesized that characterization of the early innate immune response to bacteria in the lungs would provide insight into the mechanisms used by the host to protect itself from infection. An adult mouse model of Staphylococcus aureus pneumonia was utilized to define the early events in the innate immune response and to assess the changes in the airway proteome during the first 6 h of pneumonia. S. aureus actively replicated in the lungs of mice inoculated intranasally under anesthesia to cause significant morbidity and mortality. By 6 h postinoculation, the release of proinflammatory cytokines caused effective recruitment of neutrophils to the airway. Neutrophil influx, loss of alveolar architecture, and consolidated pneumonia were observed histologically 6 h postinoculation. Bronchoalveolar lavage fluids from mice inoculated with phosphate-buffered saline (PBS) or S. aureus were depleted of overabundant proteins and subjected to strong cation exchange fractionation followed by liquid chromatography and tandem mass spectrometry to identify the proteins present in the airway. No significant changes in response to PBS inoculation or 30 min following S. aureus inoculation were observed. However, a dramatic increase in extracellular proteins was observed 6 h postinoculation with S. aureus, with the increase dominated by inflammatory and coagulation proteins. The data presented here provide a comprehensive evaluation of the rapid and vigorous innate immune response mounted in the host airway during the earliest stages of S. aureus pneumonia. | 18,852,243 |
Calcification is associated with loss of functional calcium-sensing receptor in vascular smooth muscle cells. | Vascular calcification (VC) is highly correlated with increased morbidity and mortality in advanced chronic kidney disease (CKD) patients. Allosteric modulation of the calcium-sensing receptor (CaR) by calcimimetics inhibits VC in animal models of advanced CKD. Here, we investigated the expression of the CaR in the vasculature and tested the ability of calcimimetics to prevent vascular smooth muscle cell (VSMC) calcification in vitro. Immunohistochemical staining demonstrated that CaR protein is present in VSMC in normal, non-calcified human arteries. In contrast, low levels of CaR immunoreactivity were detected in atherosclerotic, calcified arteries. Immunfluorescence and immunoblotting revealed that CaR protein was also expressed by human and bovine VSMC in vitro. Acute stimulation of VSMC with increased Ca2+ stimulated extracellular signal-regulated kinase (ERK1/2) phosphorylation, suggesting that the VSMC CaR is functional. VSMC CaR expression decreased when these cells deposited a mineralized matrix or following 24 h incubation in mineralization medium with increased (i.e. 1.8 or 2.5 mM) Ca2+. Culturing VSMC in mineralization medium containing 1.8 and 2.5 mM Ca2+ or with the membrane-impermeant CaR agonist Gd3+ enhanced mineral deposition compared with that observed in 1.2 mM Ca2+. Over-expression of dominant-negative (R185Q) CaR enhanced, whereas the calcimimetic R-568 attenuated, VSMC mineral deposition. These results demonstrate that: (i) VSMCs express a functional CaR; (ii) a reduction in CaR expression is associated with increased mineralization in vivo and in vitro; (iii) calcimimetics decrease mineral deposition by VSMC. These data suggest that calcimimetics may inhibit the development of VC in CKD patients. | 18,852,253 |
KPC-2-producing Enterobacter cloacae and pseudomonas putida coinfection in a liver transplant recipient. | Carbapenemases are among the newest resistance mechanisms to emerge in some gram-negative bacteria. We describe bacteremia in a critically ill liver transplant recipient infected with KPC-2-producing Enterobacter cloacae and Pseudomonas putida. Although this enzyme has been previously described in Enterobacter spp., this is the first report of KPC carbapenemase in P. putida. | 18,852,270 |
Lysine-enriched cecropin-mellitin antimicrobial peptides with enhanced selectivity. | Lysine-enriched analogs of the cecropin-mellitin hybrid peptide, CA(1-7) M(2-9) (designated CM15), designed with optimized amphipathicity, retained antimicrobial activities similar to that of wild-type CM15 and had substantially reduced levels of hemolytic activity and cytotoxicity toward cultured macrophages, resulting in enhanced selectivity. These lysine-enriched analogs provide templates for improved CM15 peptide or peptidomimetic antibiotics. | 18,852,279 |
BRG1-mediated chromatin remodeling regulates differentiation and gene expression of T helper cells. | During T helper cell differentiation, distinct programs of gene expression play a key role in defining the immune response to an environmental challenge. How chromatin remodeling events at the associated cytokine loci control differentiation is not known. We found that the ATP-dependent remodeling enzyme subunit BRG1 was required for T helper 2 (Th2) differentiation and Th2 cytokine transcription. BRG1 binding to cytokine genes was regulated by the extent of differentiation, the extent of activation, and cell fate. BRG1 was required for some features of the chromatin structure in target genes (DNase I hypersensitivity and histone acetylation), suggesting that BRG1 remodeling activity was directly responsible for changes in gene expression. NFAT and STAT6 activity were required for BRG1 recruitment to the Th2 locus control region, and STAT6 associated with BRG1 in a differentiation-inducible manner, suggesting direct recruitment of BRG1 to the bound loci. Together, these findings suggest BRG1 interprets differentiation signals and plays a causal role in gene regulation, chromatin structure, and cell fate. | 18,852,284 |
The HINT1 tumor suppressor regulates both gamma-H2AX and ATM in response to DNA damage. | Hint1 is a haploinsufficient tumor suppressor gene and the underlying molecular mechanisms for its tumor suppressor function are unknown. In this study we demonstrate that HINT1 participates in ionizing radiation (IR)-induced DNA damage responses. In response to IR, HINT1 is recruited to IR-induced foci (IRIF) and associates with gamma-H2AX and ATM. HINT1 deficiency does not affect the formation of gamma-H2AX foci; however, it impairs the removal of gamma-H2AX foci after DNA damage and this is associated with impaired acetylation of gamma-H2AX. HINT1 deficiency also impairs acetylation of ATM and activation of ATM and its downstream effectors, and retards DNA repair, in response to IR. HINT1-deficient cells exhibit resistance to IR-induced apoptosis and several types of chromosomal abnormalities. Our findings suggest that the tumor suppressor function of HINT1 is caused by, at least in part, its normal role in enhancing cellular responses to DNA damage by regulating the functions of both gamma-H2AX and ATM. | 18,852,295 |
Telepathology training in a master of cytology degree course. | We have investigated the changes in the workflow of the cytologist due to the introduction of telepathology. These changes occur in two stages. The first is the use of telepathology as a support methodology using external providers (i.e. outside the hospital) to digitize the slides. The second is the use of telepathology in routine laboratory operations using an internal scanner to digitize the slides. To improve courses in the Master of Cytology programme at the University of La Sapienza, new learning modules were designed, which were made available via the wide area computer network to familiarize students with the new technologies. The new methodologies had three benefits. The first was the high level of knowledge for the student. The second was the cost advantage to the student, who did not need to study in a medical laboratory to participate in the teaching. The third was the cost advantage to the hospital: as laboratories become freed from academic work, they become more available for clinical use. | 18,852,312 |
The role of technology in video-mediated consensus meetings. | We have studied the use of video-mediated technology to facilitate multidisciplinary meetings where consensus is reached about the diagnosis and treatment of patients. The meetings involved 2-5 sites, with 1-20 participants from each site, and concerned patients with severe diseases in the upper abdomen. During a period of about one year we conducted observations and interviews at the Karolinska hospital and some of the local hospitals. Eight video-mediated consensus meetings were video-recorded and transcribed. The audio and the radiology images presented during the meetings were considered to be most important; video was not critical for the consensus meeting itself, but contributed to a feeling of awareness and social presence. We conclude that video-mediated consensus meetings are affected by the technology used, and certain changes in the technology or environment could improve the meetings. Without the technology, such meetings would lead to more travelling for the patient and for the medical staff involved. | 18,852,315 |
Identity-management factors in e-health and telemedicine applications. | Reliable identification is essential in e-health and telemedicine applications. This necessitates a secure and trustworthy method of communication and collaboration between parties, which depends on common acceptance. This in turn is related to privacy and ethical matters. Different technologies, including biometrics and RFID, allow high levels of security and safety in identifying both human beings and goods. However, the diffusion of standards relating to identity management in e-health is far from satisfactory. In order to support standardization in e-health, the European Commission funded the BioHealth project. This project has proved to be useful in promoting standards and creating awareness among the stakeholders. | 18,852,323 |
Retinol-binding protein 4 in twins: regulatory mechanisms and impact of circulating and tissue expression levels on insulin secretion and action. | Retinol-binding protein (RBP) 4 is an adipokine of which plasma levels are elevated in obesity and type 2 diabetes. The aims of the study were to identify determinants of plasma RBP4 and RBP4 mRNA expression in subcutaneous adipose tissue (SAT) and skeletal muscle and to investigate the association between RBP4 and in vivo measures of glucose metabolism. The study population included 298 elderly twins (aged 62-83 years), with glucose tolerance ranging from normal to overt type 2 diabetes, and 178 young (aged 25-32 years) and elderly (aged 58-66 years) nondiabetic twins. Peripheral and hepatic insulin sensitivity was assessed by a euglycemic-hyperinsulinemic clamp, and beta-cell function was estimated from an intravenous glucose tolerance test. The influence of environmental versus genetic factors in the regulation of plasma RBP4 increased with age. Plasma RBP4 was elevated in type 2 diabetes and increased with duration of disease. Plasma RBP4 correlated inversely with peripheral, but not hepatic, insulin sensitivity. However, the association disappeared after correction for covariates, including plasma adiponectin. Plasma retinol, and not RBP4, was inversely associated with insulin secretion. SAT RBP4 expression correlated positively with GLUT4 expression and inversely with glucose tolerance. Skeletal muscle RBP4 expression reflected intramuscular fat, and although it was suppressed by insulin, no association with insulin sensitivity was evident. RBP4 expression was not associated with circulatory RBP4. In conclusion, our data indicate that RBP4 levels in plasma, skeletal muscle, and fat may be linked to insulin resistance and type 2 diabetes in a secondary and noncausal manner. | 18,852,328 |
The spectrum of parkinsonian manifestations associated with glucocerebrosidase mutations. | Mutations in the glucocerebrosidase gene (GBA) result in Gaucher disease and can be associated with a phenotype characterized by adult-onset progressive neurologic deterioration and parkinsonism. To define the clinical and neurologic spectrum of parkinsonian manifestations associated with GBA mutations. Design, Setting, and Patients A prospective case series of 10 patients (7 men and 3 women) with parkinsonism and GBA mutations evaluated at the National Institutes of Health Clinical Center. The GBA genotypes were identified by means of DNA sequencing. Tests evaluating neurologic, motor, cognitive, ocular, and olfactory functions were performed and the results were analyzed by a single team. Genotyping identified GBA mutations N370S, L444P, and c.84dupG and recombinant alleles. The mean age at onset of parkinsonian manifestations was 49 years (range, 39-65 years), disease duration was 7.8 years (range, 1.2-16.0 years), and Unified Parkinson Disease Rating Scale part III score was 26.3 (range, 13-38). Half of the patients reported cognitive changes later in the disease course. Six patients were diagnosed as having Parkinson disease, 3 as having Lewy body dementia, and 1 as having a "Parkinson plus" syndrome. The most frequent nonmotor finding was olfactory dysfunction. Atypical manifestations included myoclonus, electroencephalographic abnormalities, and seizures. In the homozygous and heterozygous states, GBA mutations are associated with a spectrum of parkinsonian phenotypes ranging from Parkinson disease, mostly of the akinetic type, to a less common phenotype characteristic of Lewy body dementia. | 18,852,351 |
Reduced selenium concentrations and glutathione peroxidase activity in preeclamptic pregnancies. | Preeclampsia is pregnancy-specific, affecting 2% to 7% of women, and is a leading cause of perinatal and maternal morbidity and mortality. Preeclampsia may also predispose the fetus to increased risks of adult cardiovascular disease. Selenium, acting through the selenoprotein glutathione peroxidases, has critical roles in regulating antioxidant status. Recent reports implicate poor maternal selenium status as a nutritional factor predisposing the mother to preeclampsia but the fetus and placenta have not been studied in tandem. Measurement of selenium concentrations, expression, and activity levels of glutathione peroxidase and markers of oxidative stress were performed on maternal and umbilical venous blood samples or the placenta from 27 normal pregnant, 25 preeclamptic, and 22 healthy age-matched nonpregnant women. The results of this study revealed highly significant reductions in serum selenium concentrations and plasma glutathione peroxidase activity in pregnancy per se compared to nonpregnant controls. Moreover, these levels were further decreased in the preeclamptic mothers and babies compared to normal pregnancies. Umbilical venous selenium was particularly low (42.1+/-11.8 and 29.0+/-9.9 microg/L; mean+/-SD; P<0.05). Both mother and baby had significantly increased levels of markers for oxidative stress in the preeclamptic group. The placental glutathione peroxidase activity and immunohistochemical staining were also reduced in the preeclampsia placentae. Oxidative stress associated with preeclampsia may be a consequence of reduced antioxidant defense pathways specifically involving glutathione peroxidases, perhaps linked to reduced selenium availability. Reduced glutathione peroxidases could be associated with increased generation of toxic lipid peroxides contributing to the endothelial dysfunction and hypertension of preeclampsia. | 18,852,388 |
The effect of smoking in midlife on health-related quality of life in old age: a 26-year prospective study. | Smoking shortens life expectancy by 7 to 10 years. However, it is unclear whether the enhanced longevity of nonsmokers produces increased disability and decreased quality of life during these extra final years. This study evaluates the long-term effect of smoking in midlife on health-related quality of life (HRQoL) in old age. Prospective cohort study with a 26-year follow-up of 1658 white men (born 1919-1934) of similar socioeconomic status who were participating in the Helsinki Businessmen Study. All men were healthy at baseline in 1974, when cardiovascular risk factors and smoking habits were assessed. The participants were reevaluated with the use of mailed questionnaires in 2000; HRQoL was measured with the use of the RAND 36-Item Health Survey (similar to the Medical Outcomes Study Short-Form Health Survey) and related to the baseline smoking status. Total mortality through 2000 was determined from Finnish national registers. Participants who had never smoked (n = 614) lived a mean of 10 years longer than heavy smokers (>20 cigarettes daily; n = 188). Among survivors in 2000 (n = 1131), the never-smokers had the highest (ie, best) scores on all RAND 36-Item Health Survey scales. The differences were greatest between never-smokers and heavy smokers, ranging from 4 points on the scale of social functioning to 14 points on the physical functioning scale. The physical component summary score showed a graded deterioration of HRQoL with an increasing number of cigarettes smoked daily (P = .01). During the 26-year follow-up of this socioeconomically homogeneous male cohort, HRQoL deteriorated with an increase in daily cigarettes smoked in a dose-dependent manner. Never-smokers lived longer than heavy smokers, and their extra years were of better quality. | 18,852,397 |
Caffeine consumption and the risk of breast cancer in a large prospective cohort of women. | Prospective data relating caffeine consumption to breast cancer risk are limited. We evaluated the association between caffeine consumption and breast cancer risk in women enrolled in a completed cancer prevention trial. Detailed dietary information was obtained at baseline (1992-1995) from 38 432 women 45 years or older and free of cancer. During a mean follow-up of 10 years, we identified 1188 invasive breast cancer cases. Consumption of caffeine and caffeinated beverages and foods was not statistically significantly associated with overall risk of breast cancer. The multivariate relative risks (RRs) of breast cancer were 1.02 (95% confidence interval [CI], 0.84-1.22) for caffeine (top vs bottom quintile), 1.08 (0.89-1.30) for coffee (> or =4 cups daily vs almost never), and 1.03 (0.85-1.25) for tea (> or =2 cups daily vs almost never). However, in women with benign breast disease, a borderline significant positive association with breast cancer risk was observed for the highest quintile of caffeine consumption (RR, 1.32; 95% CI, 0.99-1.76) and for the highest category of coffee consumption (> or =4 cups daily) (1.35; 1.01-1.80); tests for interaction were marginally significant. Caffeine consumption was also significantly positively associated with risk of estrogen receptor-negative and progesterone receptor-negative breast cancer (RR, 1.68; 95% CI, 1.01-2.81) and breast tumors larger than 2 cm (1.79; 1.18-2.72). These data show no overall association between caffeine consumption and breast cancer risk. The possibility of increased risk in women with benign breast disease or for tumors that are estrogen and progesterone receptor negative or larger than 2 cm warrants further study. | 18,852,405 |
Risk of admission to a nursing home among older people with visual impairment in Great Britain. | To assess the risk of nursing home admission in a representative sample of older, visually impaired, community-dwelling people 75 years and older living in Great Britain. Prospective study. General practices (n = 53). Participants in the Medical Research Council trial of assessment and management of older people in the community (N = 14 037). Main Outcome Measure Nursing home admission (nursing or residential care). After a mean of 4 years' follow-up, 14.1% of visually impaired participants were living in nursing homes (95% confidence interval [CI], 11.9%-16.3%; age- and sex-adjusted risk ratio, 1.47 [95% CI, 1.25-1.73]). Adjusting for a wide range of confounding factors eliminated this significant association (risk ratio, 1.08 [95% CI, 0.91-1.28]). The association between visual impairment and risk of nursing home admission was eliminated after controlling for a wide range of other confounding factors and comorbidities. This underlines the importance of taking a wider view of an older person's health rather than focusing on a single impairment or disability. | 18,852,422 |
Herpetic encephalitis is a risk factor for acute retinal necrosis. | Acute retinal necrosis (ARN) has been observed in several cases after herpetic encephalitis (HE). ARN is a devastating ocular disease with a very disappointing visual outcome. Therefore, early recognition and diagnosis are crucial. To study the association between ARN and preceding neurologic illness, especially the co-occurrence of HE in patients with ARN; to compare the causal agent in ARN and HE; and to determine the visual outcome of ARN with HE vs ARN without HE. A retrospective study including ophthalmologic and neurologic follow-up together with virologic data of patients with ARN. Seven patients with ARN diagnosed with a history of HE (13.5%) out of a source population of 52 patients with ARN admitted to a major academic ophthalmologic referral center between 1983 and 2008. In five out of seven patients unilateral ARN occurred after HE under immunocompetent conditions, and both ARN and HE were caused by the herpes simplex virus (HSV), whereas the other two patients were immunocompromised, had bilateral ARN, and both ARN and HE were caused by the varicella zoster virus (VZV). The latency period between the HE and the ARN was shorter when VZV was involved than with HSV (5 weeks vs 20.6 months). The visual outcome in patients with ARN with HE, as defined by legally blind eyes after a follow-up of 1 year, did not differ significantly from patients with ARN without HE. Herpetic encephalitis seems to be a risk factor for acute retinal necrosis syndrome. Since treatment may improve the outcome at least for the second eye, it is relevant for clinicians to be aware of this association. | 18,852,442 |
DNA variation and symbiotic associations in phenotypically diverse sea urchin Strongylocentrotus intermedius. | Strongylocentrotus intermedius (A. Agassiz, 1863) is an economically important sea urchin inhabiting the northwest Pacific region of Asia. The northern Primorye (Sea of Japan) populations of S. intermedius consist of two sympatric morphological forms, "usual" (U) and "gray" (G). The two forms are significantly different in morphology and preferred bathymetric distribution, the G form prevailing in deeper-water settlements. We have analyzed the genetic composition of the S. intermedius forms using the nucleotide sequences of the mitochondrial gene encoding the cytochrome c oxidase subunit I and the nuclear gene encoding bindin to evaluate the possibility of cryptic species within S. intermedius. We have examined the presence of symbiont microorganisms by means of 16S rRNA sequences. The nucleotide sequence divergence between the morphological forms is low: 0.74% and 0.70% for cytochrome c oxidase subunit I and nuclear gene encoding bindin, respectively, which is significantly below average intrageneric sequence divergence among Strongylocentrotus species. We thus have found no genetic evidence of cryptic species within S. intermedius. Phylogenetic analysis shows that the bacteria symbionts of S. intermedius belong to the phylum Bacteroidetes, but the U and G forms predominantly harbor highly divergent bacterial lineages belonging to two different taxonomic classes, Flavobacteria and Sphingobacteria. We propose that the U and G forms of S. intermedius represent distinct ecomorphological adaptations to contrasting shallow- and deep-water marine environments and might be considered incipient species. We also propose that the symbiotic bacteria likely play an important role in the evolution of morphological divergence of S. intermedius. | 18,852,450 |
Crystallographic snapshots of eukaryotic dimethylallyltransferase acting on tRNA: insight into tRNA recognition and reaction mechanism. | Hypermodifications near the anticodon of tRNA are fundamental for the efficiency and fidelity of protein synthesis. Dimethylallyltransferase (DMATase) catalyzes transfer of a dimethylallyl moiety from dimethylallyl pyrophosphate to N6 of A37 in certain tRNAs. Here we present the crystal structures of Saccharomyces cerevisiae DMATase-tRNA(Cys) complex in four distinct forms, which provide snapshots of the RNA modification reaction catalyzed by DMATase. The structures reveal that the enzyme recognizes the tRNA substrate through indirect sequence readout. The targeted nucleotide A37 flips out from the anticodon loop of tRNA and flips into a channel in DMATase, where it meets its reaction partner di methylallyl pyrophosphate, which enters the channel from the opposite end. Structural changes accompanying the transfer reaction taking place in the crystal result in disengagement of DMATase-tRNA interaction near the reaction center. In addition, structural comparison of DMATase in the complex with unliganded bacterial DMATase provides a molecular basis of ordered substrate binding by DMATase. | 18,852,462 |
Theory, analysis, and interpretation of single-molecule force spectroscopy experiments. | Dynamic force spectroscopy probes the kinetic and thermodynamic properties of single molecules and molecular assemblies. Here, we propose a simple procedure to extract kinetic information from such experiments. The cornerstone of our method is a transformation of the rupture-force histograms obtained at different force-loading rates into the force-dependent lifetimes measurable in constant-force experiments. To interpret the force-dependent lifetimes, we derive a generalization of Bell's formula that is formally exact within the framework of Kramers theory. This result complements the analytical expression for the lifetime that we derived previously for a class of model potentials. We illustrate our procedure by analyzing the nanopore unzipping of DNA hairpins and the unfolding of a protein attached by flexible linkers to an atomic force microscope. Our procedure to transform rupture-force histograms into the force-dependent lifetimes remains valid even when the molecular extension is a poor reaction coordinate and higher-dimensional free-energy surfaces must be considered. In this case the microscopic interpretation of the lifetimes becomes more challenging because the lifetimes can reveal richer, and even nonmonotonic, dependence on the force. | 18,852,468 |
Potent HIV fusion inhibitors against Enfuvirtide-resistant HIV-1 strains. | T20 (generic name: Enfuvirtide, brand name: Fuzeon) is the only FDA-approved HIV fusion inhibitor that is being used for treatment of HIV/AIDS patients who have failed to respond to current antiretroviral drugs. However, it rapidly induces drug resistance in vitro and in vivo. On the basis of the structural and functional information of anti-HIV peptides from a previous study, we designed an HIV fusion inhibitor named CP32M, a 32-mer synthetic peptide that is highly effective in inhibiting infection by a wide range of primary HIV-1 isolates from multiple genotypes with R5- or dual-tropic (R5X4) phenotype, including a group O virus (BCF02) that is resistant to T20 and C34 (another anti-HIV peptide). Strikingly, CP32M is exceptionally potent (at low picomolar level) against infection by a panel of HIV-1 mutants highly resistant to T20 and C34. These findings suggest that CP32M can be further developed as an antiviral therapeutic against multidrug resistant HIV-1. | 18,852,475 |
Time-resolved and two-photon emission imaging microscopy of live cells with inert platinum complexes. | This work explores time-resolved emission imaging microscopy (TREM) for noninvasive imaging and mapping of live cells on a hitherto uncharted microsecond time scale. Simple robust molecules for this purpose have long been sought. We have developed highly emissive, synthetically versatile, and photostable platinum(II) complexes that make TREM a practicable reality. [PtLCl], {HL = 1,3-di(2-pyridyl)benzene and derivatives}, are charge-neutral, small molecules that have low cytotoxicity and accumulate intracellularly within a remarkably short incubation time of 5 min, apparently under diffusion control. Their microsecond lifetimes and emission quantum yields of up to 70% are exceptionally high for transition metal complexes and permit the application of TREM to be demonstrated in a range of live cell types-normal human dermal fibroblast, neoplastic C8161 and CHO cells. [PtLCl] are thus likely to be suitable emission labels for any eukaryotic cell types. The high photostability of [PtLCl] under intense prolonged irradiation has allowed the development of tissue-friendly NIR two-photon excitation (TPE) in conjunction with transition metal complexes in live cells. A combination of confocal one-photon excitation, nonlinear TPE, and microsecond time-resolved imaging has revealed (i) preferential localization of the complexes to intracellular nucleic acid structures, in particular the nucleoli and (ii) the possibility of measuring intracellular emission lifetimes in the microsecond range. The combination of TREM, TPE, and Pt(II) complexes will be a powerful tool for investigating intracellular processes in vivo, because the long lifetimes allow discrimination from autofluorescence and open up the use of commonplace technology. | 18,852,476 |
Function of the Bacillus subtilis transcription elongation factor NusG in hairpin-dependent RNA polymerase pausing in the trp leader. | NusA and NusG are transcription elongation factors that bind to RNA polymerase (RNAP) after sigma subunit release. Escherichia coli NusA (NusA(Ec)) stimulates intrinsic termination and RNAP(Ec) pausing, whereas NusG(Ec) promotes Rho-dependent termination and pause escape. Both Nus factors also participate in the formation of RNAP(Ec) antitermination complexes. We showed that Bacillus subtilis NusA (NusA(Bs)) stimulates intrinsic termination and RNAP(Bs) pausing at U107 and U144 in the trpEDCFBA operon leader. Pausing at U107 and U144 participates in the transcription attenuation and translational control mechanisms, respectively, presumably by providing additional time for trp RNA-binding attenuation protein (TRAP) to bind to the nascent trp leader transcript. Here, we show that NusG(Bs) causes modest pause stimulation at U107 and dramatic pause stimulation at U144. NusA(Bs) and NusG(Bs) act synergistically to increase the U107 and U144 pause half-lives. NusG(Bs)-stimulated pausing at U144 requires RNAP(Bs), whereas NusA(Bs) stimulates pausing of RNAP(Bs) and RNAP(Ec) at the U144 and E. coli his pause sites. Although NusG(Ec) does not stimulate pausing at U144, it competes with NusG(Bs)-stimulated pausing, suggesting that both proteins bind to the same surface of RNAP(Bs). Inactivation of nusG results in the loss of RNAP pausing at U144 in vivo and elevated trp operon expression, whereas plasmid-encoded NusG complements the mutant defects. Overexpression of nusG reduces trp operon expression to a larger extent than overexpression of nusA. | 18,852,477 |
Bevacizumab improves the overall and progression-free survival of patients with metastatic colorectal cancer treated with 5-fluorouracil-based regimens irrespective of baseline risk. | Kohne et al. [Ann Oncol 2002;13:308-317] showed that four prognostic variables can be used to classify patients with metastatic colorectal cancer (CRC) treated with 5-fluorouracil (5-FU)/leucovorin (LV) into three risk groups with different overall survival (OS). This model was applied to data from phase II/III trials of first-line bevacizumab plus 5-FU/LV with/without irinotecan (IFL). Data on tumor sites, Eastern Cooperative Oncology Group performance status, alkaline phosphatase levels and white blood cell counts were used to classify patients into Kohne prognostic high-, intermediate- and low-risk groups. Median OS and progression-free survival (PFS) were calculated for patients receiving 5-FU/LV plus bevacizumab or placebo (n = 489) and IFL plus bevacizumab or placebo (n = 812). Median OS was longer in 5-FU/LV/bevacizumab (11.2-22.6 months) than in the 5-FU/LV/placebo (5.7-17.5 months), and in the IFL/bevacizumab arm (14.3-22.5 months) than in the IFL/placebo arm (8.4-17.9 months) across the Kohne high-, intermediate- and low-risk groups. The addition of bevacizumab also extended median PFS across the Kohne risk groups compared with placebo. Bevacizumab improves OS and PFS across the Kohne risk classification in patients with metastatic CRC. The Kohne model can be extended to patients treated with 5-FU/LV/bevacizumab, IFL and IFL/bevacizumab and to PFS data. | 18,852,492 |
Morphogenetic behavior of tropical marine yeast Yarrowia lipolytica in response to hydrophobic substrates. | The morphogenetic behavior of a tropical marine Yarrowia lipolytica strain on hydrophobic substrates was studied. Media containing coconut oil or palm kernel oil (rich in lauric and myristic acids) prepared in distilled water or seawater at a neutral pH supported 95% of the cells to undergo a transition from the yeast form to the mycelium form. With potassium laurate, 51% of the cells were in the mycelium form, whereas with myristate, 32% were in the mycelium form. However, combinations of these two fatty acids in proportions that are present in coconut oil or palm kernel oil enhanced the mycelium formation to 65%. The culture also produced extracellular lipases during the morphogenetic change. The yeast cells were found to attach to the large droplets of the hydrophobic substrates during the transition, while the mycelia were associated with the aqueous phase. The alkane-grown yeast partitioned more efficiently in the hydrophobic phases when compared with the coconut oil-grown mycelia. A fatty acid analysis of the mycelial form revealed the presence of lauric acid in addition to the long-chain saturated and unsaturated fatty acids observed in the yeast form. The mycelia underwent a rapid transition to the yeast form with n-dodecane, a medium-chain aliphatic hydrocarbon. Thus, the fungus displayed a differential behavior towards the two types of saturated hydrophobic substrates. | 18,852,507 |
Beneficial effects of fluorescent pseudomonads on seed germination, growth promotion, and suppression of charcoal rot in groundnut (Arachis hypogea L.). | Rhizobacteria are used as inoculants to enhance crop yield and for biological control of fungal pathogens. Fluorescent pseudomonads isolated from the rhizosphere of groundnut showed suppression of the phytopathogen Macrophomina phaseolina that causes charcoal rot of groundnut, an economically important agroproduct. Two strains of fluorescent pseudomonads, designated as PS1 and PS2, were selected as a result of in vitro antifungal activity. After 5 days of incubation at 28+/-1 degrees , both PS1 and PS2 caused clear inhibition zones in dual cultures, restricting the growth of M. phaseolina by 71% and 74%, respectively. Both the strains were capable of producing siderophores, indole acetic acid, and hydrocyanic acid, and causing phosphate solubilization under normal growth conditions. These strains, when used as inoculants in groundnut, enhanced germination up to 15% and 30% with subsequent increase in grain yield by 66% and 77%, respectively. Conversely, when the pathogen alone was testeds 57% decrease in yield was recorded. Thus the studies revealed the potential of the two pseudomonads not only as biocontrol agents against M. phaseolina, but also as a good growth promoter for groundnut. | 18,852,515 |
Relationship of physical function to vastus lateralis capillary density and metabolic enzyme activity in elderly men and women. | There are no data showing whether or not age-related declines in physical function are related to in vitro properties of human skeletal muscle. The purpose of this study was to determine whether physical function is independently associated with histologic and metabolic properties of skeletal muscle in elderly adults. The study was a cross-sectional observational study of 39 sedentary, older (60-85 yrs) men and women. A needle biopsy of the vastus lateralis for assessment of muscle fiber type, fiber area, capillary density and citrate synthase and aldolase activities was performed. Physical function tests included the Short Physical Performance Battery (balance, walking speed, and chair rise time), as well as self-reported disability. Total fiber area (R=-0.41, p=0.02), number of Type II fibers (R=-0.33, p=0.05), and aldolase activity (R=-0.54, p=0.01) were inversely related to age. Persons who reported greater difficulty with daily activities had lower capillary density (R=-0.51, p=0.03) and lower citrate synthase activity (R=-0.66, p=0.03). Walking speed was directly related to fiber area (R=0.40, p=0.02), capillary density (R=0.39, p=0.03), citrate synthase (R=0.45, p=0.03) and aldolase (R=0.55, p<0.01) activities, even after adjustment for age, BMI and disease status. In older adults, skeletal muscle capillary density and metabolic enzymatic activity are independent predictors of lower extremity physical function. | 18,852,542 |
Rehabilitative outcome in supratentorial and infratentorial stroke: the role of motor deficits. | There are few studies on the functional outcome of patients with supratentorial (STS) and infratentorial stroke (ITS). They lead to conflicting conclusions and do not define the role of motor deficits on functional recovery of STS and ITS patients. We wished to investigate this. The study was carried out on 90 consecutive patients admitted to our Rehabilitation Department with clinical evidence of acute cerebrovascular accident. Neuroimaging data, clinical evidence, and the National Institute of Health Stroke Scale (NIH) were used to select two groups of patients: 1) 45 patients with supratentorial stroke lesion (STS group), 2) 45 patients with infratentorial stroke lesion (ITS group). The STS group included patients with hemiparesis, and the ITS group patients with ataxia. Patients were evaluated through the NIH, Fugl-Meyer scale, Klockgether score, CIRS, Trunk Control Test (TCT), Lindmark scale, Barthel index, and Katz index, at both admission and discharge. At admission, there were no differences between the STS and ITS groups in disability or average Barthel, Lindmark and Katz scores. At discharge, the Katz index average scores were significantly higher (p=0.000) and disability was lower (p=0.002) in ITS patients. The efficiency in Lindmark, Barthel and Katz scores of group ITS was significantly greater than that of STS patients (p=0.003, p=0.030 and p=0.000, respectively). The final Katz score was correlated (Spearman rank method) with initial TCT (p=0.000), onset to admission interval (p=0.019) and initial NIH (p=0.044) in the STS group. Final BADL score was correlated only with initial TCT (p=0.000) in the ITS group. Our data seem to indicate that STS has a worse rehabilitative prognosis than ITS, and that hemiparesis is more difficult to rehabilitate than ataxia. | 18,852,543 |
Vitamin D supplementation has no major effect on pain or pain behavior in bedridden geriatric patients with advanced dementia. | In a few, earlier, uncontrolled trials, alleviation of chronic pain has been documented by vitamin D supplementation. This randomized double-blind placebo controlled trial addressed the association between pain and vitamin D deficiency and the effects of vitamin D supplementation on pain in institutionalized aged patients. 216 long-term care patients were enrolled in Helsinki, Finland. Pain was assessed by three tools: Resident Assessment Instrument (RAI), Discomfort Behavior Scale, and Pain Assessment in Advanced Dementia Scale. Scores for Cognitive Performance Scale (CPS) and other clinical assessments were also collected from the RAI-database. Levels of 25-hydroxyvitamin D (25- OHD) and parathyroid hormone were also determined. Patients in pain (n=202) were randomized into three treatment groups, each receiving 0, 400, or 1200 IU cholecalciferol per day, respectively. Assessments were repeated after six-month vitamin D supplementation. Patients were aged (84.5+/-7.5 yrs), demented (CPS= 4.9+/-1.4, range 1-6), and chronically bedridden. Pain was present in 38.4% to 83.8% of patients depending on assessment tool. Low 25-OHD levels (<50 nmol/L) were very common (98.1%). However, vitamin D deficiency was not associated with pain or pain behavior. The supplementation resulted in a marked increase in 25-OHD levels. However, neither prevalence of painlessness nor pain scores changed significantly after vitamin D supplementation. We were not able either to show an association between vitamin D deficiency and pain or to observe alleviation of pain by vitamin D supplementation. The independent role of vitamin D in the etiology of pain remains controversial. | 18,852,544 |
Mental health economics, health service provision, and the practice of geriatric psychiatry. | Economic evaluation is becoming more and more important as a means to assist policy makers in choosing the best intervention or treatment against a pervasive scarcity of resources relative to the demands. Health service provision and the practice of geriatric psychiatry are closely associated with costs and outcomes of health economics. Recently published literature raising unanswered questions in these areas is reviewed. Some studies on the costs, outcomes, and cost-effectiveness of certain interventions or treatments (e.g. respite care, home-visiting community service) compared with usual strategies show that these are not optimal in terms of health economics. The updated guidance by the National Institute for Health and Clinical Excellence that cholinesterase inhibitors should be used only for moderate severity dementia on the grounds of cost-effectiveness has been heavily criticized. Mental health provision for older people varies across 'developed' and 'developing' countries. Updated findings provide better understanding of recent progress and issues on mental health economics, health service provision, and the practice of geriatric psychiatry. The application of health economics to the field of mental health should make complicated issues simple and explicit. Constructive criticisms and scientific debates will hasten the development of better tools or methodologies to evaluate the cost-effectiveness of current and new interventions or treatments. | 18,852,560 |
Cultural and social history of psychiatry. | The purpose of this review is to highlight recent English language literature in the cultural and social history of psychiatry. It considers publications from 2007 and early 2008, as well as a few important older works that have not yet been reviewed in this journal. Cultural and social historians of psychiatry are incorporating a growing number of historical objects into their narratives and developing new methodological techniques that can accommodate the full diversity of psychiatry's hybrid past. Increasingly, these histories are coming to be written in terms of multilateral and multivalent interactions with various other disciplines and organizations. In crafting these new narratives, historians face a confusing panoply of historical agents and events, reminding them that like the discipline of psychiatry itself, theirs too is a heterologic undertaking, grappling to understand and explain the otherness of psychiatry's past. This review surveys the scholarly literature in several specific areas that have attracted the attention of historians of psychiatry in recent years. In particular, it considers work in the history of psychiatric institutions, borderline disorders, 20th-century somatic therapies, military psychiatry, and colonial psychiatry. | 18,852,566 |
Cardiomyopathy induced by adenosine-insensitive atrial tachycardia. | Tachycardia-induced cardiomyopathy may be provoked by several arrhythmias; it may reverse following stable restoration of sinus rhythm. We report the case of a 33-year-old man who was diagnosed to have a dilated cardiomyopathy. Over a few months, the cardiomyopathy reversed. Subsequently, atrial tachycardia, associated with a recurrent impairment of left ventricular function, occurred. Adenosine infusion during atrial tachycardia caused transient atrioventricular block without the interruption of arrhythmia, which is consistent with a micro-reentrant mechanism. Electroanatomic mapping during tachycardia showed a focus arising from the left superior pulmonary vein ostium. After successful catheter ablation of the focus, left ventricular function fully recovered. | 18,852,591 |
An uncommon case of right-sided throat pain and swallow syncope. | A 63-year-old man presented with recurrent syncopal attacks associated with swallowing and right-sided throat pain. Immediately after admission, he presented a 16-s asystolia. The patient's clinical history was unremarkable except for previous postimplant periodontitis. Several episodes of severe bradycardia and sinus pauses, always associated with painful deglutition, were recorded subsequently. X-ray orthopanthomography and magnetic resonance imaging of the neck confirmed several areas of periodontitis around the previous dental implants and right mastoid inflammation. A barium swallow and fibre-optic endoscopy also revealed a small sliding hiatus hernia and distal chronic oesophageal inflammation. Despite complete dental curettage, antibiotics and antigastro-oesophageal reflux therapy, only partial relief of the pain and incomplete resolution of the arrhythmic disorder were obtained after 3 weeks, and the patient underwent pacemaker implantation. At 1-month follow-up, however, he reported the complete relief of the throat pain; subsequent Holter monitoring showed normal sinus rhythm, without pacemaker-induced electrical activity. | 18,852,592 |
The decline of cardiac auscultation: 'the ball of the match point is poised on the net'. | A brief review of the history of cardiac auscultation confirms its decline. The intervention of healthcare institutions may avoid loss of medical culture and increased costs by adequate training of medical staff. | 18,852,598 |
Implicit and explicit stigma of mental illness: links to clinical care. | This study examined implicit and explicit measures of bias toward mental illness among people with different levels of mental health training, and investigated the influence of stigma on clinically-relevant decision-making. Participants (N = 1539) comprised of (1) mental health professionals and clinical graduate students, (2) other health care/social services specialists, (3) undergraduate students, and (4) the general public self-reported their attitudes toward people with mental illness, and completed implicit measures to assess mental illness evaluations that exist outside of awareness or control. In addition, participants predicted patient prognoses and assigned diagnoses after clinical vignettes. Compared with people without mental health training, individuals with mental health training demonstrated more positive implicit and explicit evaluations of people with mental illness. Further, explicit (but not implicit) biases predicted more negative patient prognoses, but implicit (and not explicit) biases predicted over-diagnosis, underscoring the value of using both implicit and explicit measures. | 18,852,619 |
Cytokeratin 18, a marker of cell death, is increased in children with suspected nonalcoholic fatty liver disease. | Nonalcoholic fatty liver disease (NAFLD) is a chronic liver disease associated with obesity, and is now the most common liver disease in the United States. Cytokeratin 18 (CK18) is an intracellular protein released into the blood by both necrosis and apoptosis of hepatocytes. Levels of CK18 have not been reported previously in children with NAFLD. In a cross-sectional analysis of 62 children (28 normal weight, 14 obese, and 20 suspected NAFLD), we measured CK18 levels as well as alanine aminotransferase, fasting glucose, fasting insulin, and tumor necrosis factor-alpha. CK18 was significantly elevated in the children with suspected NAFLD compared with obese controls and normal weight controls (median = 424 U/L compared with 243 and 214 respectively, P < 0.001). In multiple logistic regression analysis, CK18 was the best single predictor of suspected NAFLD (prediction accuracy = 84.1%). CK18 is elevated in children with suspected NAFLD and should be investigated as a potential diagnostic marker of NAFLD. | 18,852,641 |
ABO incompatible living renal transplantation with a steroid sparing protocol. | ABO incompatible (ABOi) live-donor renal transplantation is a successful and accepted form of treatment for patients with renal failure. Although there is significant controversy as to how antiblood group antibodies should be removed and their resynthesis prevented, subsequent immunosuppressive regimes have all involved steroids. We and other groups have successfully used steroid sparing regimes for conventional ABO compatible transplantation and this study describes the use of our steroid sparing protocol in ABOi transplantation. We have transplanted 10 ABOi patients using 1 week of steroids (prednisolone 1 mg/kg for 4 days, 0.5 mg/kg for 3 days and then stopped), tacrolimus and mycophenolate mofetil. Steroids were reintroduced in the event of rejection. Patient- and allograft-survival 1 year posttransplantation is 100%. Three patients experienced antibody-mediated rejection within 2 weeks of transplantation, which was successfully reversed. There has been no late rejection. Allograft function was similar to our live-donor ABO compatible transplant patients receiving a similar steroid sparing regime (12-month mean creatinine 131+/-15 micromol/L vs. 138+/-48 micromol/L; mean CrCl 63.2+/-22 mL/min vs. 56.7+/-20 mL/min). This study shows that ABOi live-donor transplantation can be successfully accomplished using a steroid-sparing protocol. | 18,852,653 |
Collagenase penetrates human pancreatic islets following standard intraductal administration. | : To optimize human islet isolation, it is important to improve our understanding of the collagenase digestion phase. Previous studies of collagenase action were mostly concerned with optimizing its composition, but the delivery and distribution of collagenase at the islet-exocrine interface is likely to be important for liberation of intact islets. The aim of this study was to characterize collagenase distribution in relation to islets in infused human pancreases. : Human pancreases were retrieved from multiorgan donors with appropriate consent. Tissue samples were taken from the neck, body, and tail regions before and after collagenase infusion by manual syringe-loading (n=10) or recirculating perfusion (n=8), and snap frozen in liquid nitrogen. Frozen sections were immunolabeled for collagenase, insulin, CK19, collagen VI and CD31, then assessed by confocal microscopy. : Collagenase labeling was widespread throughout the pancreas, associated with collagen VI, and adjacent to CK19-labeled ducts. Collagenase was found within 67%+/-2% of islets ("intraislet"), associated with capillaries (CD31-positive). Intraislet collagenase was observed in 70%+/-3% of islets in the pancreatic tail, compared with 58%+/-2% and 53%+/-2% of islets in the body and neck, respectively (P<0.05 tail vs. neck), and was more prevalent in islets with diameters more than 150 microm (98%+/-1% of islets >150 microm vs. 52%+/-2% of islets <150 microm, P<0.05). There was no difference in intraislet collagenase labeling between perfused and syringe-loaded pancreases. : Using current infusion techniques, collagenase penetrates the islet interior. This could cause islet fragmentation, and consequently, low islet yields. This study underlies the need to optimize collagenase delivery to preserve intact islets. | 18,852,654 |
Epithelioid hemangioma of bone revisited: a study of 50 cases. | The clinical and pathologic features of 50 epithelioid hemangiomas of bone are analyzed. There were 29 males and 21 females who ranged in age from 10 to 75 (mean 35) years. The tumors arose in long tubular bones (40%), short tubular bones of the distal lower extremity (18%), flat bones (18%), vertebrae (16%), and small bones of the hands (8%). Nine patients (18%) had involvement of more than 1 bone. Radiographically, the lesions were lucent and well marginated. Microscopically, the neoplasms had a lobular architecture and were composed of epithelioid endothelial cells that formed obvious vascular lumina or grew in solid sheets. No hyalinized or solid appearing extracellular myxoid matrix was present. Thirty-five patients were treated with curettage, 13 patients had a local resection and 2 patients only had a biopsy. One patient had local lymph node involvement. Three patients were treated with surgery and radiation therapy. Follow-up information revealed that 4 patients experienced a local recurrence; and 1 patient developed limited involvement of a regional lymph node. Epithelioid hemangioma of bone is a benign lesion that may be multifocal and affect separate tissue and is successfully treated with curettage or marginal en bloc excision. | 18,852,673 |
Structural remodeling in atrial fibrillation. | Atrial fibrillation occurs and maintains itself in the context of a morphologically and functionally altered atrial substrate that can be induced by stressors such as underlying diseases (cardiac or noncardiac) or aging. The resultant structural remodeling is a slow process that progressively affects myocytes and the myocardial interstitium, and takes place from as early as the first days of atrial tachyarrhythmia. The left atrium, and particularly its posterior wall, is the location where remodeling is concentrated to the greatest extent. The mechanisms that underlie the remodeling process in atrial fibrillation have not yet been completely elucidated, although experimental and clinical investigations have indicated a number of signaling systems, inflammation, oxidative stress, atrial stretching and ischemia as factors involved in the cascade of events that leads to atrial fibrillation. The aim of this Review is to provide a comprehensive overview of the morphological changes that characterize the fibrillating atrial myocardium at histological and ultrastructural levels, and the established and hypothetical pathogenetic mechanisms involved in structural remodeling. This article also highlights the emerging therapies being developed to prevent progression of atrial fibrillation. | 18,852,714 |
Duloxetine and pregabalin: safe and effective for the long-term treatment of fibromyalgia? | This Practice Point commentary discusses the first two trials of long-term drug treatment in fibromyalgia. In Russell et al.'s study, 33% of patients receiving 6-month treatment with 60 mg/day duloxetine responded to therapy; the number needed to treat was seven. In the three treatment arms, 15% (60 mg/day duloxetine), 27% (120 mg/day duloxetine) and 13% (placebo) of patients discontinued treatment because of adverse events (the most common being nausea [24%] and fatigue [14%]). In Crofford et al.'s study, 32% of patients who received pregabalin had loss of therapeutic response, compared with 61% of patients treated with placebo. The discontinuation rate due to adverse events (dizziness in 36% of cases and somnolence in 22%) during the randomized treatment phase was 16% with pregabalin and 7% with placebo. This commentary discusses the implications of these trials for clinical practice and considers areas for future research in the field. In view of the current results, duloxetine and pregabalin could be administered together and as part of multimodal and multidisciplinary therapy, but treatment should 'start low and go slow'. | 18,852,724 |
Highly nonlinear silica suspended core fibers. | Suspended-core fibers are systematically studied. We show that confinement loss in suspended-core fibers can be effectively reduced by an increase of air-cladding width for even sub-micron core diameters and, therefore, provides a considerable simpler solution than equivalent photonic crystal fibers with a large number of air holes for a wide range of nonlinear applications. We have further demonstrated a suspended-core silica fiber with core diameters of 1.27 microm and sub-dB splice loss to Hi1060. Loss at 1.55 microm was measured in this fiber to be 0.078 dB/m, a record for this small core diameter, limited mainly by scattering loss at the glass and air interface. The combination of high nonlinearity, low splice loss and low transmission loss of the suspended core silica fibers will enable a new class of low loss all-fiber nonlinear devices. | 18,852,748 |
Rapid and inexpensive fabrication of terahertz electromagnetic bandgap structures. | Modern rapid prototyping technologies are now capable of build resolutions that allow direct fabrication of photonic structures in the GHz and THz frequency regimes. To demonstrate this, we have fabricated several structures with 3D electromagnetic bandgaps in the 100-400 GHz range. Characterization of these structures via THz Time-domain Spectroscopy (THz-TDS) shows very good agreement with simulation, confirming the build accuracy of the approach. This rapid and inexpensive 3-D fabrication method may be very useful for a variety of potential THz applications. | 18,852,750 |
Time fluctuations of the phase modulation in a liquid crystal on silicon display: characterization and effects in diffractive optics. | In this paper we provide evidence of the temporal fluctuations of the phase modulation property of a liquid crystal on silicon (LCoS) display, and we analyze its effect when the device is used for displaying a diffractive optical element. We use a commercial twisted nematic LCoS display configured to produce a phase-only modulation, and we provide time resolved measurements of the diffraction efficiency that show rapid fluctuations of the phase modulation, in the millisecond order. We analyze how these fluctuations have to be considered in two typical methods for the characterization of the phase modulation: two beam interference and diffraction from a binary grating. We finally provide experimental results on the use of this device for displaying a computer generated hologram. A reduction of the modulation diffraction efficiency results from the phase modulation fluctuation. | 18,852,780 |
Fabrication of thermally stable and cost-effective polymeric waveguide for optical printed-circuit board. | A thermally stable polymeric optical waveguide has been fabricated using ultraviolet (UV)-curable epoxy resins for the core and clad materials. A simple and cost-effective fabrication method that uses reusable polydimethylsiloxane (PDMS) masters has been developed. The 12-channel under-clad layer of the UV-cured epoxy was prepared using a PDMS master whose embossed channels had been fabricated by a polycarbonate (PC) secondary master. The thermal stability of the fabricated waveguide was tested at 200 degrees C for one hour. The optical waveguide was not damaged physically by thermal stress. Propagation losses detected by a cut-back method were 0.16 dB/cm and 0.26 dB/cm, respectively, before and after the thermal stability test at 850 nm. Loss increase after the thermal treatment can be attributed to the formation of the absorbing and scattering sources. This waveguide can be applied for areas that require thermal stability such as an optical printed-circuit board. | 18,852,788 |
Unusual entanglement transformation properties of the quantum radiation through one-dimensional random system containing left-handed-materials. | The quantum radiation through the multilayer structures containing the left-handed materials is investigated based on the Green-function approach to the quantization of the phenomenological Maxwell theory. Emphasis is placed on the effect of randomness on the generation and transmission of entangled-states. It is shown that some unusual properties appear for the present systems in comparison with those of the conventional dielectric structures. The quantum relative entropy is always enhanced with the increase of random degree due to the existence of nonlocalized mode in the present systems, while the maximal entanglement can be observed only at some certain randomness for the conventional dielectric structures. In contrast to exponential decrease in the conventional systems, the entanglement degrades slowly with the increase of disorder and thickness of the sample near the nonlocalized mode after transmission through the present systems. This will benefit the quantum communication for long distances. | 18,852,803 |
Fast and simple characterization of a photon pair source. | We present an exact model of the detection statistics of a probabilistic source of photon pairs from which a fast, simple and precise method to measure the source's brightness and photon channel transmissions is demonstrated. We measure such properties for a source based on spontaneous parametric downconversion in a periodically poled LiNbO(3) crystal producing pairs at 810 and 1550 nm wavelengths. We further validate the model by comparing the predicted and measured values for the g((2))(0) of a heralded single photon source over a wide range of the brightness. Our model is of particular use for monitoring and tuning the brightness on demand as required for various quantum communication applications. We comment on its applicability to sources involving spectral and/or spatial filtering. | 18,852,816 |
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