title stringlengths 0 1.13k | abstract stringlengths 1 15.7k | PMID int64 22 36.5M |
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7-[1H-Indol-2-yl]-2,3-dihydro-isoindol-1-ones as dual Aurora-A/VEGF-R2 kinase inhibitors: design, synthesis, and biological activity. | A novel series of 7-[1H-indol-2-yl]-2,3-dihydro-isoindol-1-ones designed to be inhibitors of VEGF-R2 kinase was synthesized and found to potently inhibit VEGF-R2 and Aurora-A kinases. The structure-based design, synthesis, and initial SAR of the series are discussed. | 18,718,756 |
Extracellular matrix rigidity promotes invadopodia activity. | Invadopodia are actin-rich subcellular protrusions with associated proteases used by cancer cells to degrade extracellular matrix (ECM) [1]. Molecular components of invadopodia include branched actin-assembly proteins, membrane trafficking proteins, signaling proteins, and transmembrane proteinases [1]. Similar structures exist in nontransformed cells, such as osteoclasts and dendritic cells, but are generally called podosomes and are thought to be more involved in cell-matrix adhesion than invadopodia [2-4]. Despite intimate contact with their ECM substrates, it is unknown whether physical or chemical ECM signals regulate invadopodia function. Here, we report that ECM rigidity directly increases both the number and activity of invadopodia. Transduction of ECM-rigidity signals depends on the cellular contractile apparatus [5-7], given that inhibition of nonmuscle myosin II, myosin light chain kinase, and Rho kinase all abrogate invadopodia-associated ECM degradation. Whereas myosin IIA, IIB, and phosphorylated myosin light chain do not localize to invadopodia puncta, active phosphorylated forms of the mechanosensing proteins p130Cas (Cas) and focal adhesion kinase (FAK) are present in actively degrading invadopodia, and the levels of phospho-Cas and phospho-FAK in invadopodia are sensitive to myosin inhibitors. Overexpression of Cas or FAK further enhances invadopodia activity in cells plated on rigid polyacrylamide substrates. Thus, in invasive cells, ECM-rigidity signals lead to increased matrix-degrading activity at invadopodia, via a myosin II-FAK/Cas pathway. These data suggest a potential mechanism, via invadopodia, for the reported correlation of tissue density with cancer aggressiveness. | 18,718,759 |
Traditional versus endoscopic saphenous vein stripping: a prospective randomized pilot trial. | The aim of this pilot study was to compare two methods of removing the great saphenous vein (GSV) from the groin to the limit of distal venous incompetence. Our aim was to compare endoscopically assisted GSV stripping to conventional stripping. Randomised pilot study. 60 patients presenting with primary GSV incompetence and symptomatic varicose veins were randomly assigned to sapheno-ligation and either conventional GSV stripping or endoscopically assisted GSV stripping. The primary endpoint was the number of adverse events including haematoma in the thigh, ecchymosis, seroma, wound healing complications and wound infections. The SF-36 health survey was completed before treatment and one and four weeks postoperatively. The study was approved by the local ethics committee (EK 07-041-VK). 60 patients were enrolled in the study and randomized to endoscopic (n=30) and to traditional (n=30) stripping. The patients age ranged from 30 to 75 years (mean 53 years), 18 patients were male, 42 female. The combined rate of postoperative morbidity at week 1 was 32 events (53%), 13 (42%) events in the endoscopic and 19 (63%) in the conventional group (not significant). The SF-36 assessment one week postoperatively showed that patients in the endoscopic group reported significantly less pain (P=0.03, Mann-Whitney). At four weeks, patients in the endoscopic group had significantly less pain (P<0.005) and better physical function (P<0.005) and physical role (P=0.01). For all other parameters no significant difference noted. The results of this study suggest that endoscopic GSV excision showed no difference in adverse events between treatments, although our pilot study may have been under-powered to demonstrate this. The SF-36 assessment suggests more rapid return to normal activities post-operatively in the endoscopic group. | 18,718,770 |
Abdominal aortic aneurysm development in men following a "normal" aortic ultrasound scan. | To determine predictors related to abdominal aortic aneurysm (AAA) development following a "normal" aortic ultrasound scan. Over a 23-year period, 22 961 men participated in an AAA screening programme. Maximum aortic diameter of less than 30 mm was deemed "normal". 4308 of these "normal" individuals were later re-scanned at intervals for research purposes. AAA prevalence was 4.4% at initial scanning. In those with a normal scan, 46 patients subsequently presented with AAAs incidentally detected and 120 (2.8%) had AAAs identified as part of the ongoing surveillance. The median initial aortic size of these 166 men was 25 mm (range 15-29 mm). Over the follow-up period, there have been 24 (14%) AAA-related deaths, 24 patients underwent successful AAA surgery and 36 died of unrelated causes. In those with an initial aortic diameter of <25 mm who later developed an AAA, the odds ratio for AAA-related mortality was 2 (95% CI 1-4.1, p=0.03, x(2)). AAAs can develop following an initial "normal" scan and men with an aortic diameters of 25-29 mm appear to be at greater risk. Surveillance for this sub-group may further reduce the incidence of undiagnosed AAA and AAA-related mortality. | 18,718,773 |
Comparison of stability of titanium and absorbable plate and screw fixation for mandibular angle fractures. | The purpose of this experimental study was to compare the stability of titanium and absorbable plate and screw fixation systems for mandibular angle fractures. Twenty-one sheep hemimandibles were used to evaluate 3 different plating techniques. The groups were fixated with a single titanium plate, a single absorbable plate and double absorbable plates. A cantilever bending biomechanical test model was used for the samples. Each group was tested with vertical forces by a servohydraulic testing unit. The displacement values in each group at each 10 N stage up to 100 N were compared using the 2-way analysis of variance test. The displacement values for the 3 groups differed significantly (P < .05). The variance analyses showed that titanium plate placement had more favorable biomechanical behavior than others. In addition, the 2 absorbable plates group had more favorable biomechanical behavior than a single absorbable plate group but it was not significantly different at 10 to 40 N. The study demonstrated that titanium plate and screw fixation system had greater resistance to occlusal loads than absorbable plate and screw systems. In addition, a second absorbable plate orientation provides a more favorable biomechanical behavior than a single absorbable plate placement. | 18,718,777 |
Histopathologic features of oral submucous fibrosis: a study of 35 biopsy specimens. | This study was carried out principally to confirm the diagnosis of Oral Submucous Fibrosis, to provide a more detailed description of the Histopathological changes occurring in OSMF and to look for and record any new finding which might be detected. For this reason only previously untreated cases were selected for biopsy. Patients reporting at Liaquat University Hospital, Dental Out Patient Department, Hyderabad, Sindh, Pakistan. 35 biopsy specimens were obtained from patients presenting with Oral Submucous Fibrosis reporting prior to receiving any instructions or management and still using areca nut preparations in some form. Patients with overt malignancy were not included in this study. Histopathological analysis was carried out to confirm the disease and to evaluate the microscopic features of Oral Submucous Fibrosis (OSMF). Diffuse nonspecific chronic inflammation with fibrosis was present in all specimens (100%). Classical picture of OSMF was found in 20 (57.4%) of specimens while 16 (45.7%) showed Lichenoid reaction as well. OSMF with ulceration was present in 14 (40%) specimens. Pseudoepitheliomatous hyperplasia was recorded in 9 (25.7%). Dysplastic changes were seen in 3 (8.6%) specimens. This study gives a detailed account of the histological changes along with the frequency of their occurrence and describes a new finding of Lichenoid reaction occurring in OSMF. | 18,718,788 |
Cell-cycle deregulation induced by three different root canal sealers in vitro. | The aim of this study was to investigate the effects of 3 root canal sealers on the cell cycle of mouse fibroblasts (3T3 cell line). Freshly mixed root canal sealers (AH Plus, Endofill, and Sealer 26) were eluted for 24 h using cell culture medium. Antiproliferation activity of different eluate dilutions was determined by 3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide assay. Cell cycle was subsequently evaluated by flow cytometry. Differences were tested by analysis of variance with Tukey test (P < .05). Results showed that the root canal sealers inhibited cell growth in a dose-dependent manner. Antiproliferation activity of the root canal sealers was associated with cell-cycle deregulation. This event involved cell-cycle arrest in the S/G2/M phases and an increase of the sub-G1 population, which are consistent with both cytostatic and cytotoxic effects. This information may contribute to a better understanding of the toxicity mechanism displayed by root canal sealers currently used in clinical practice. | 18,718,791 |
Observer reliability of three-dimensional cephalometric landmark identification on cone-beam computerized tomography. | To evaluate reliability in 3-dimensional (3D) landmark identification using cone-beam computerized tomography (CBCT). Twelve presurgery CBCTs were randomly selected from 159 orthognathic surgery patients. Three observers independently repeated 3 times the identification of 30 landmarks in the sagittal, coronal, and axial slices. A mixed-effects analysis of variance model estimated the intraclass correlations (ICC) and assessed systematic bias. The ICC was >0.9 for 86% of intraobserver assessments and 66% of interobserver assessments. Only 1% of intraobserver and 3% of interobserver coefficients were <0.45. The systematic difference among observers was greater in X and Z than in Y dimensions, but the maximum mean difference was quite small. Overall, the intra- and interobserver reliability was excellent. Three-dimensional landmark identification using CBCT can offer consistent and reproducible data if a protocol for operator training and calibration is followed. This is particularly important for landmarks not easily specified in all 3 planes of space. | 18,718,796 |
A clinical, neuropsychological and olfactory evaluation of a large family with LRRK2 mutations. | We evaluated the neurological and neuropsychological profiles and olfaction as presymptomatic markers in a large family with Parkinson disease (PD) caused by the G2019S mutation in the LRRK2 gene. Five affected family members, 14 asymptomatic mutation carriers and 15 non-carriers were compared. Patients had typical dopa-responsive PD, frequently associated with cognitive impairment. Asymptomatic carriers and non-carriers could not be distinguished because of their neuropsychological status, the presence of depression or olfactory impairment. We were therefore unable to identify a presymptomatic marker of LRRK2-related PD. | 18,718,805 |
A common gene pool for the Neisseria FetA antigen. | Meningococcal FetA is an iron-regulated, immunogenic outer membrane protein and vaccine component. The most diverse region of this protein is a previously defined variable region (VR) that has been shown to be immunodominant. In this analysis, a total of 275 Neisseria lactamica isolates, collected during studies of nasopharyngeal bacterial carriage in infants, were examined for the presence of a fetA gene. The fetA VR nucleotide sequence was determined for 217 of these isolates, with fetA apparently absent from 58 isolates, the majority of which belonged to the ST-624 clonal complex. The VR in N. lactamica was compared to the same region in N. meningitidis, N. gonorrhoeae, and a number of other commensal Neisseria. Identical fetA variable region sequences were identified among commensal and pathogenic Neisseria, suggesting a common gene pool, differing from other antigens in this respect. Carriage of commensal Neisseria species, such as N. lactamica, that express FetA may be involved in the development of natural immunity to meningococcal disease. | 18,718,812 |
Neutralizing host responses in hepatitis C virus infection target viral entry at postbinding steps and membrane fusion. | Hepatitis C virus (HCV) is a leading cause of chronic hepatitis worldwide. Viral attachment and entry, representing the first steps of virus-host cell interactions, are major targets of adaptive host cell defenses. The mechanisms of antibody-mediated neutralization by host neutralizing responses in HCV infection are only poorly understood. Retroviral HCV pseudotypes (HCVpp) and recombinant cell culture-derived HCV (HCVcc) have been successfully used to study viral entry and antibody-mediated neutralization. In this study, we used these model systems to investigate the mechanism of antibody-mediated neutralization by monoclonal antienvelope antibodies and polyclonal anti-HCV immunoglobulins purified from HCV-infected patients. Using a panel of monoclonal antienvelope antibodies, we identified an epitope within the E1 glycoprotein targeted by human neutralizing antibodies during postbinding events. Interestingly, we observed that host neutralizing responses in the majority of HCV-infected individuals include antibodies targeting HCV entry after binding of the virus to the target cell membrane. Using a kinetic assay based on HCVpp and HCVcc entry, we demonstrate that purified antiviral immunoglobulins derived from individual HCV-infected patients appear to inhibit HCV infection at an entry step closely linked to CD81 and scavenger receptor BI (SR-BI). Our results indicate that host neutralizing responses in HCV-infected patients target viral entry after HCV binding most likely related to HCV-CD81, and HCV-SR-BI interactions, as well as membrane fusion. These findings have implications not only for the understanding of the pathogenesis of HCV infection but also for the design of novel immunotherapeutic and preventive strategies. | 18,718,838 |
Tityus serrulatus venom peptidomics: assessing venom peptide diversity. | MALDI-TOF-TOF and de novo sequencing were employed to assess the Tityus serrulatus venom peptide diversity. Previous works has shown the cornucopia of molecular masses, ranging from 800 to 3000Da, present in the venom from this and other scorpions species. This work reports the identification/sequencing of several of these peptides. The majority of the peptides found were fragments of larger venom toxins. For instance, 28 peptides could be identified as fragments from Pape proteins, 10 peptides corresponded to N-terminal fragments of the TsK beta (scorpine-like) toxin and fragments of potassium channel toxins (other than the k-beta) were sequenced as well. N-terminal fragments from the T. serrulatus hypotensins-I and II and a novel hypotensin-like peptide could also be found. This work also reports the sequencing of novel peptides without sequence similarities to other known molecules. | 18,718,845 |
Alternative splicing in the NF-kappaB signaling pathway. | Activation of transcription factor NF-kappaB can affect the expression of several hundred genes, many of which are involved in inflammation and immunity. The proper NF-kappaB transcriptional response is primarily regulated by post-translational modification of NF-kappaB signaling constituents. Herein, we review the accumulating evidence suggesting that alternative splicing of NF-kappaB signaling components is another means of controlling NF-kappaB signaling. Several alternative splicing events in both the tumor necrosis factor and Toll/interleukin-1 NF-kappaB signaling pathways can inhibit the NF-kappaB response, whereas others enhance NF-kappaB signaling. Alternative splicing of mRNAs encoding some NF-kappaB signaling components can be induced by prolonged exposure to an NF-kappaB-activating signal, such as lipopolysaccharide, suggesting a mechanism for negative feedback to dampen excessive NF-kappaB signaling. Moreover, some NF-kappaB alternative splicing events appear to be specific for certain diseases, and could serve as therapeutic targets or biomarkers. | 18,718,859 |
Acute behavioural and neurotoxic effects of MDMA plus cocaine in adolescent mice. | The poly-drug pattern is the most common among those observed in MDMA users, with cocaine being a frequently associated drug. This study evaluates the acute effects of MDMA (5, 10 and 20 mg/kg), alone or in combination with cocaine (25 mg/kg), on motor activity, anxiety (elevated plus maze and social interaction test), memory and brain monoamines in adolescent mice. Both drugs, administered alone or concurrently, produced hyperactivity and a decrease in social contacts. However, an anxiolytic effect, studied by means of the elevated plus maze and expressed as an increase in the time spent on the open arms, was observed only in those animals treated with cocaine and MDMA. The passive avoidance task was affected only with the highest MDMA dose (20 mg/kg). Mice treated with MDMA did not present significant changes in brain monoamines, while those receiving MDMA and cocaine showed a decrease in DA in the striatum, which was accompanied by an increase in the serotonin concentration in the striatum and cortex 30 min after acute administration. In conclusion, the combined use of MDMA and cocaine produces a predominance of serotonin over DA, which is associated with an anxiolytic profile, defensive behaviours and fewer social contacts. | 18,718,862 |
Depletion of central BDNF in mice impedes terminal differentiation of new granule neurons in the adult hippocampus. | Granule neurons generated in the adult mammalian hippocampus synaptically integrate to facilitate cognitive function and antidepressant efficacy. Here, we investigated the role of BDNF in facilitating their maturation in vivo. We found that depletion of central BDNF in mice elicited an increase in hippocampal cell proliferation without affecting cell survival or fate specification. However, new mutant neurons failed to fully mature as indicated by their lack of calbindin, reduced dendritic differentiation and an accumulation of calretinin(+) immature neurons in the BDNF mutant dentate gyrus. Furthermore, the facilitating effects of GABA(A) receptor stimulation on neurogenesis were absent in the mutants, suggesting that defects might be due to alterations in GABA signaling. Transcriptional analysis of the mutant hippocampal neurogenic region revealed increases in markers for immature neurons and decreases in neuronal differentiation facilitators. These findings demonstrate that BDNF is required for the terminal differentiation of new neurons in the adult hippocampus. | 18,718,867 |
Mental health correlates of intimate partner violence in marital relationships in a nationally representative sample of males and females. | It is important to understand the epidemiology of intimate partner violence (IPV) experienced by both males and females. Data were drawn from the U.S. National Comorbidity Survey Replication. The relationships between physical IPV and child abuse, mental disorders, and suicidal ideation and attempts among males and females were examined. The results indicate that child sexual abuse was associated with IPV among males, whereas child physical and sexual abuse was associated with IPV among females. IPV was associated with poor mental health outcomes for males and females, although sex differences are noted. The sex differences indicate that females experience a wider range of poor mental health outcomes compared to males. Knowledge about correlates of IPV can be useful in identifying individuals exposed to violence. Further research is required to identify effective methods to reduce exposure to IPV and to adequately address the specific needs of male and female victims of IPV. | 18,718,882 |
Development and daily use of an electronic oncological patient record for the total management of cancer patients: 7 years' experience. | We describe our experience with an electronic oncological patient record (EOPR) for the total management of cancer patients. The web-based EOPR was developed on the basis of a user-centred design including user education and training, followed by continuous assistance; user acceptance was monitored by means of three questionnaires administered after 2 weeks, 6 months and 6 years. The EOPR has been used daily for all in-ward, day hospital and ambulatory clinical activities since July 2000. The most widely appreciated functions are its rapid multipoint access, the self-updated summary of the patients' clinical course, the management of the entire therapeutic programme synchronised with working agendas and oncological teleconsultation. Security and privacy are assured by means of the separate storage of clinical and demographic data, with access protected by login and a password. The questionnaires highlighted appreciation of rapid data retrieval and exchange and the perception of improved quality of care, but also revealed a sense of additional work and a negative impact on doctor-patient relationships. Our EOPR has proved to be effective in the total management of cancer patients. Its user-centred design and flexible web technology have been key factors in its successful implementation and daily use. | 18,718,889 |
Expression of stathmin, a microtubule regulatory protein, is associated with the migration and differentiation of cultured early trophoblasts. | The microtubule-destabilizing protein stathmin is expressed by the villous cytotrophoblasts and invasive extravillous trophoblasts (EVTs) in the first-trimester human placenta. Here, we evaluated the significance of stathmin expression in terms of the functions of trophoblasts. We employed two choriocarcinoma cell lines (BeWo and JEG-3), an EVT cell line (HTR-8/SVneo) and isolated first-trimester trophoblast cells. The effects of small-interfering (si) RNA-mediated stathmin knockdown on trophoblast proliferation and migration were measured by WST-1 and Transwell assays, respectively. Trophoblast differentiation was induced by dibutyryl (db)-cAMP treatment and evaluated by measuring human chorionic gonadotrophin beta (hCGbeta) and syncytin expression and cell fusion. We examined the effect of knockdown and induced stathmin expression on db-cAMP-induced differentiation. siRNA-induced silencing of stathmin expression had a marked inhibitory effect on BeWo, JEG-3 and HTR-8/SVneo cell migration and also suppressed their proliferation, albeit to a lesser extent. db-cAMP-enhanced hCGbeta and syncytin expression and cell fusion in BeWo cells was inhibited by stathmin knockdown. However, induced expression of stathmin reversed the hCGbeta and syncytin expression and cell fusion in the Tet-On BeWo cells. Suppression of stathmin expression also inhibited the migration of and hCGbeta production by first-trimester trophoblasts. Stathmin expression may be closely associated with early trophoblast migration and differentiation into syncytiotrophoblasts during placentation. | 18,718,898 |
Positive selection in ASPM is correlated with cerebral cortex evolution across primates but not with whole-brain size. | The rapid increase of brain size is a key event in human evolution. Abnormal spindle-like microcephaly associated (ASPM) is discussed as a major candidate gene for explaining the exceptionally large brain in humans but ASPM's role remains controversial. Here we use codon-specific models and a comparative approach to test this candidate gene that was initially identified in Homo-chimp comparisons. We demonstrate that accelerated evolution of ASPM (omega = 4.7) at 16 amino acid sites occurred in 9 primate lineages with major changes in relative cerebral cortex size. However, ASPM's evolution is not correlated with major changes in relative whole-brain or cerebellum sizes. Our results suggest that a single candidate gene such as ASPM can influence a specific component of the brain across large clades through changes in a few amino acid sites. We furthermore illustrate the power of using continuous phenotypic variability across primates to rigorously test candidate genes that have been implicated in the evolution of key human traits. | 18,718,919 |
Biochemical analysis of the N-terminal domain of human RAD54B. | The human RAD54B protein is a paralog of the RAD54 protein, which plays important roles in homologous recombination. RAD54B contains an N-terminal region outside the SWI2/SNF2 domain that shares less conservation with the corresponding region in RAD54. The biochemical roles of this region of RAD54B are not known, although the corresponding region in RAD54 is known to physically interact with RAD51. In the present study, we have biochemically characterized an N-terminal fragment of RAD54B, consisting of amino acid residues 26-225 (RAD54B(26-225)). This fragment formed a stable dimer in solution and bound to branched DNA structures. RAD54B(26-225) also interacted with DMC1 in both the presence and absence of DNA. Ten DMC1 segments spanning the entire region of the DMC1 sequence were prepared, and two segments, containing amino acid residues 153-214 and 296-340, were found to directly bind to the N-terminal domain of RAD54B. A structural alignment of DMC1 with the Methanococcus voltae RadA protein, a homolog of DMC1 in the helical filament form, indicated that these RAD54B-binding sites are located near the ATP-binding site at the monomer-monomer interface in the DMC1 helical filament. Thus, RAD54B binding may affect the quaternary structure of DMC1. These observations suggest that the N-terminal domain of RAD54B plays multiple roles of in homologous recombination. | 18,718,930 |
Stability and kinetics of G-quadruplex structures. | In this review, we give an overview of recent literature on the structure and stability of unimolecular G-rich quadruplex structures that are relevant to drug design and for in vivo function. The unifying theme in this review is energetics. The thermodynamic stability of quadruplexes has not been studied in the same detail as DNA and RNA duplexes, and there are important differences in the balance of forces between these classes of folded oligonucleotides. We provide an overview of the principles of stability and where available the experimental data that report on these principles. Significant gaps in the literature have been identified, that should be filled by a systematic study of well-defined quadruplexes not only to provide the basic understanding of stability both for design purposes, but also as it relates to in vivo occurrence of quadruplexes. Techniques that are commonly applied to the determination of the structure, stability and folding are discussed in terms of information content and limitations. Quadruplex structures fold and unfold comparatively slowly, and DNA unwinding events associated with transcription and replication may be operating far from equilibrium. The kinetics of formation and resolution of quadruplexes, and methodologies are discussed in the context of stability and their possible biological occurrence. | 18,718,931 |
Protective role of Engrailed in a Drosophila model of Huntington's disease. | Huntington's disease (HD) is caused by the expansion of the polyglutamine (polyQ) tract in the human Huntingtin (hHtt) protein (polyQ-hHtt). Although this mutation behaves dominantly, htt loss of function may also contribute to HD pathogenesis. Using a Drosophila model of HD, we found that Engrailed (EN), a transcriptional activator of endogenous Drosophila htt (dhtt), is able to prevent aggregation of polyQ-hHtt. To interpret these findings, we tested and identified a protective role of N-terminal fragments of both Drosophila and Human wild-type Htt onto polyQ-hHtt-induced cellular defects. In addition, N-terminal parts of normal hHtt were also able to rescue eye degeneration due to the loss of Drosophila endogenous dhtt function. Thus, our data indicate that Drosophila and Human Htt share biological properties, and confirm a model whereby EN activates endogenous dhtt, which in turn prevents polyQ-hHtt-induced phenotypes. The protective role of wild-type hHtt N-terminal parts, specifically onto polyQ-hHtt-induced cellular toxicity suggests that the HD may be considered as a dominant negative disease rather than solely dominant. | 18,718,937 |
Rtreemix: an R package for estimating evolutionary pathways and genetic progression scores. | In genetics, many evolutionary pathways can be modeled by the ordered accumulation of permanent changes. Mixture models of mutagenetic trees have been used to describe disease progression in cancer and in HIV. In cancer, progression is modeled by the accumulation of chromosomal gains and losses in tumor cells; in HIV, the accumulation of drug resistance-associated mutations in the viral genome is known to be associated with disease progression. From such evolutionary models, genetic progression scores can be derived that assign measures for the disease state to single patients. Rtreemix is an R package for estimating mixture models of evolutionary pathways from observed cross-sectional data and for estimating associated genetic progression scores. The package also provides extended functionality for estimating confidence intervals for estimated model parameters and for evaluating the stability of the estimated evolutionary mixture models. | 18,718,947 |
Multi-dimensional classification of biomedical text: toward automated, practical provision of high-utility text to diverse users. | Much current research in biomedical text mining is concerned with serving biologists by extracting certain information from scientific text. We note that there is no 'average biologist' client; different users have distinct needs. For instance, as noted in past evaluation efforts (BioCreative, TREC, KDD) database curators are often interested in sentences showing experimental evidence and methods. Conversely, lab scientists searching for known information about a protein may seek facts, typically stated with high confidence. Text-mining systems can target specific end-users and become more effective, if the system can first identify text regions rich in the type of scientific content that is of interest to the user, retrieve documents that have many such regions, and focus on fact extraction from these regions. Here, we study the ability to characterize and classify such text automatically. We have recently introduced a multi-dimensional categorization and annotation scheme, developed to be applicable to a wide variety of biomedical documents and scientific statements, while intended to support specific biomedical retrieval and extraction tasks. The annotation scheme was applied to a large corpus in a controlled effort by eight independent annotators, where three individual annotators independently tagged each sentence. We then trained and tested machine learning classifiers to automatically categorize sentence fragments based on the annotation. We discuss here the issues involved in this task, and present an overview of the results. The latter strongly suggest that automatic annotation along most of the dimensions is highly feasible, and that this new framework for scientific sentence categorization is applicable in practice. | 18,718,948 |
Survey on chest drainage systems adopted in Europe. | The aim of this survey, promoted by the European Society of Thoracic Surgeons, was to acquire information and advice from 'the field' in order to promote development of technology for thoracic surgery and to provide information for future guidelines on chest drainage. Society members were offered a questionnaire on the European Society of Thoracic Surgeons website (November 2006) composed of seven sections comprehending 21 detailed items. The questionnaire was completed by 120 centres, 100% performed lung surgery, 91.6% mediastinal surgery, 54.1% oesophageal surgery, 10% cardiothoracic surgery. The PVC straight drain (mean 55.9%) and silicon drain (mean 38.4%), water-valve/water suction disposable chest drainage collection system (mean 43.4%), one bottle (mean 24.8%), and two bottles with suction control (mean 18.2%), were the most frequently used. After pneumonectomy 51.2% used a balanced drainage system, 9% periodical thoracocentesis, 39.8% others. In 57.5-92% drainage suction was stopped <or=4 postoperative days and in 8-42.5% >4 postoperative days. In 17.6-60.7% drains were removed <or=4 postoperative days and in 39.3-82.4% >4 postoperative days. The survey demonstrates a trend toward the use of updated technical devices, high consideration of the costs, and clinical practice based on personal preferences. | 18,718,956 |
Intracellular phospholipase A(2) group IVA and group VIA play important roles in Wallerian degeneration and axon regeneration after peripheral nerve injury. | We provide evidence that two members of the intracellular phospholipase A(2) family, namely calcium-dependent group IVA (cPLA(2) GIVA) and calcium-independent group VIA (iPLA(2) GVIA) may play important roles in Wallerian degeneration in the mouse sciatic nerve. We assessed the roles of these PLA(2)s in cPLA(2) GIVA(-/-) mice, and mice treated with a selective inhibitor of iPLA(2) GVIA (FKGK11). Additionally, the effects of both these PLA(2)s were assessed by treating cPLA(2) GIVA(-/-) mice with the iPLA(2) inhibitor. Our data suggest that iPLA(2) GVIA may play more of a role in the early stages of myelin breakdown, while cPLA(2) GIVA may play a greater role in myelin clearance by macrophages. Our results also show that the delayed myelin clearance and Wallerian degeneration after sciatic nerve crush injury in mice lacking cPLA(2) and iPLA(2) activities is accompanied by a delay in axon regeneration, target re-innervation and functional recovery. These results indicate that the intracellular PLA(2)s (cPLA(2) GIVA and iPLA(2) GVIA) contribute significantly to various aspects of Wallerian degeneration in injured peripheral nerves, which is then essential for successful axon regeneration. This work has implications for injury responses and recovery after peripheral nerve injuries in humans, as well as for understanding the slow clearance of myelin after CNS injury and its potential consequences for axon regeneration. | 18,718,965 |
Reviewing evidence on complex social interventions: appraising implementation in systematic reviews of the health effects of organisational-level workplace interventions. | The reporting of intervention implementation in studies included in systematic reviews of organisational-level workplace interventions was appraised. Implementation is taken to include such factors as intervention setting, resources, planning, collaborations, delivery and macro-level socioeconomic contexts. Understanding how implementation affects intervention outcomes may help prevent erroneous conclusions and misleading assumptions about generalisability, but implementation must be adequately reported if it is to be taken into account. Data on implementation were obtained from four systematic reviews of complex interventions in workplace settings. Implementation was appraised using a specially developed checklist and by means of an unstructured reading of the text. 103 studies were identified and appraised, evaluating four types of organisational-level workplace intervention (employee participation, changing job tasks, shift changes and compressed working weeks). Many studies referred to implementation, but reporting was generally poor and anecdotal in form. This poor quality of reporting did not vary greatly by type or date of publication. A minority of studies described how implementation may have influenced outcomes. These descriptions were more usefully explored through an unstructured reading of the text, rather than by means of the checklist. Evaluations of complex interventions should include more detailed reporting of implementation and consider how to measure quality of implementation. The checklist helped us explore the poor reporting of implementation in a more systematic fashion. In terms of interpreting study findings and their transferability, however, the more qualitative appraisals appeared to offer greater potential for exploring how implementation may influence the findings of specific evaluations. Implementation appraisal techniques for systematic reviews of complex interventions require further development and testing. | 18,718,981 |
Does low-field dedicated extremity MRI (E-MRI) reliably detect bone erosions in rheumatoid arthritis? A comparison of two different E-MRI units and conventional radiography with high-resolution CT scanning. | To compare the ability of two different E-MRI units and conventional radiography (CR) to identify bone erosions in rheumatoid arthritis (RA) metacarpophalangeal (MCP) and wrist joints with CT scanning as the standard reference method. 20 patients with RA and 5 controls underwent CR, CT and two E-MRI examinations (Esaote Biomedica Artoscan and MagneVu MV1000) of one hand during a 2-week period. In all modalities, each bone of the wrist and MCP joints was blindly evaluated for erosions. MagneVu images were also assessed for the proportion of each bone being visualised. 550 bones were examined. CT, Artoscan, MagneVu and CR detected 188, 116, 55 and 45 bones with erosions, respectively. The majority were located in the carpal bones. The sensitivity of the Artoscan for detecting erosions was higher than that of the MagneVu and CR (MCP joints: 0.68, 0.54 and 0.57, respectively; wrists: 0.50, 0.23 and 0.29). Corresponding specificities for detecting erosions were 0.94, 0.93 and 0.99, respectively, in the MCP joints and 0.92, 0.98 and 0.98 in the wrist. The MagneVu allowed visualisation of 1.5 cm of the ventral-dorsal diameter of the bone. In the wrist, 31.6% of bones were visualised entirely and 37.9% of bones were 67-99% visualised. In MCP joints, 84.2% of bones were visualised entirely and 15.8% of bones were 67-99% visualised. With CT as the reference method for detecting erosions in RA hands, the Artoscan showed higher sensitivity than the MagneVu and CR. All imaging modalities had high specificities. The better performance of the Artoscan should be considered when selecting an imaging method in RA. | 18,718,987 |
Liquid in the gastroesophageal segment promotes reflux, but compliance does not: a mathematical modeling study. | The mechanical force relationships that distinguish normal from chronic reflux at sphincter opening are poorly understood and difficult to measure in vivo. Our aim was to apply physics-based computer simulations to determine mechanical pathogenesis of gastroesophageal reflux. A mathematical model of the gastroesophageal segment (GES) was developed, incorporating the primary anatomical and physiomechanical elements that drive GES opening and reflux. In vivo data were used to quantify muscle stiffness, sphincter tone, and gastric pressure. The liquid lining the mucosa was modeled as an "effective liquid film" between the mucosa and a manometric catheter. Newton's second law was solved mathematically, and the space-time details of opening and reflux were predicted for systematic variations in gastric pressure increase, film thickness, muscle stiffness, and tone. "Reflux" was defined as "2 ml of refluxate entering the esophagus within 1 s." GES opening and reflux were different events. Both were sensitive to changes in gastric pressure and sphincter tone. Reflux initiation was extremely sensitive to the liquid film thickness; the protective function of the sphincter was destroyed with only 0.4 mm of liquid in the GES. Compliance had no effect on reflux initiation, but affected reflux volume. The presence of abnormal levels of liquid within the collapsed GES can greatly increase the probability for reflux, suggesting a mechanical mechanism that may differentiate normal reflux from gastroesophageal reflux disease. Compliance does not affect the probability for reflux, but affects reflux volume once it occurs. Opening without reflux suggests the existence of "gastroesophageal pooling" in the distal esophagus, with clinical implications. | 18,718,998 |
Nuclear factor-kappaB mediates the inhibitory effects of tumor necrosis factor-alpha on growth hormone-inducible gene expression in liver. | TNF inhibits serine protease inhibitor 2.1 (Spi 2.1) and IGF-I gene expression by GH in CWSV-1 hepatocytes. The current study describes construction of a GH-inducible IGF-I promoter construct and investigates mechanisms by which TNF and nuclear factor-kappaB (NFkappaB) inhibit GH-inducible gene expression. CWSV-1 cells were transfected with GH-inducible Spi 2.1 or IGF-I promoter luciferase constructs, incubated with TNF signaling inhibitors (fumonisin B1 for sphingomyelinase and SP600125 for c-Jun N-terminal kinase), treated with or without TNF, and then stimulated with recombinant human GH. The 5- to 6-fold induction of Spi 2.1 and IGF-I promoter activity by GH was inhibited by TNF. Neither fumonisin B1 nor SP600125 prevented the inhibitory effects of TNF on GH-inducible promoter activity. Dominant-negative inhibitor-kappaBalpha (IkappaBalpha) expression vectors (IkappaBalphaS/A or IkappaBalphaTrunc), p65 and p50 expression vectors, and p65 deletion constructs were used to investigate the NFkappaB pathway. IkappaBalphaS/A and IkappaBalphaTrunc ameliorated the inhibitory effects of TNF on GH-inducible Spi 2.1 and IGF-I promoter activity. Cotransfection of CWSV-1 cells with expression vectors for p65 alone or p50 and p65 together inhibited GH-inducible Spi 2.1 and IGF-I promoter activity. Cotransfection with a C-terminal p65 deletion (1-450) enhanced GH-inducible promoter activity, whereas the N-terminal deletion (31-551) was inhibitory for IGF-I but not Spi 2.1. Cycloheximide did not antagonize the inhibitory effects of TNF on GH-inducible IGF-I expression. We conclude the inhibitory effects of TNF on GH-inducible promoter activity are mediated by NFkappaB, especially p65, by a mechanism that does not require protein synthesis. | 18,719,026 |
Safety and efficacy of adjunctive balloon remodeling during endovascular treatment of intracranial aneurysms: a literature review. | Concurrent temporary inflation of a nondetachable balloon in the parent artery has been reported to be useful during endovascular coiling of complex, wide-neck aneurysms, facilitating truer coil reconstruction of the native vessel. Nevertheless, there exists concern that adjunctive use of balloon assistance may lead to increased adverse events during aneurysm coiling. A literature search of all of the unassisted and balloon-remodeling studies published between 1997 and 2006 was conducted with application of strict selection criteria based on the reporting of complication incidence and outcome. The final cohort was analyzed to determine rates and clinical outcomes of iatrogenic aneurysm rupture and thromboembolism. Additional data were collected on the degree of initial and follow-up aneurysm occlusion rates. A total of 83 potential studies (4973 patients) were identified, from which 23 articles reporting results for 867 traditional-unassisted and 273 balloon-assisted coiled aneurysms met inclusion criteria for the analysis of thromboembolic complications, and 21 articles with 993 routinely coiled and 170 balloon-remodeled aneurysms were eligible for iatrogenic perforation analysis. No statistically significant difference was found in the rates of thromboembolism. Iatrogenic perforation rates were also comparable, though the overall numbers were too few for meaningful statistical analysis. Both initial and follow-up aneurysm occlusion rates were higher in balloon-assisted cases. This largest-to-date literature review and meta-analysis did not demonstrate a higher incidence of thromboembolic events or iatrogenic rupture with the use of adjunctive balloon remodeling compared with unassisted coiling. Balloon remodeling appears to result in higher initial and follow-up aneurysm occlusion rates. | 18,719,039 |
Asenapine induces differential regional effects on serotonin receptor subtypes. | Asenapine, a novel psychopharmacologic agent being developed for the treatment of schizophrenia and bipolar disorder, has high affinity for a wide range of receptors, including the serotonergic receptors 5-HT(1A), 5-HT(1B), 5-HT(2A), 5-HT( 2B), 5-HT(2C), 5-HT(5A), 5-HT(6) and 5-HT( 7). We examined the long-term effects in rat brain of multiple doses of asenapine on representative serotonin receptor subtypes: 5-HT(1A), 5-HT(2A) and 5-HT(2C). Rats were given asenapine (0.03, 0.1 or 0.3 mg/kg) subcutaneously twice daily or vehicle for 4 weeks. Brain sections were collected from the medial prefrontal cortex (mPFC), dorsolateral frontal cortex (DFC), caudate putamen, nucleus accumbens, hippocampal CA( 1) and CA(3) regions, and entorhinal cortex and processed for in-vitro receptor autoradiography. Asenapine 0.1 and 0.3 mg/kg significantly increased 5-HT(1A) binding in mPFC (by 24% and 33%, respectively), DFC (27%, 31%) and hippocampal CA(1) region (23%, 25%) (all P < 0.05). All three asenapine doses (0.03, 0.1 and 0.3 mg/kg) significantly decreased 5-HT(2A) binding by a similar degree in mPFC (40%, 44%, 47%, respectively) and DFC (45%, 51%, 52%) (all P < 0.05), but did not alter 5-HT(2A) binding in the other brain regions studied. In contrast to the effects on 5-HT(1A) and 5-HT(2A) receptors, asenapine did not alter 5-HT(2C) binding in any brain region examined at the doses tested. Our results indicate that repeated administration of asenapine produces regional-specific effects on 5-HT(1A) and 5-HT(2A) receptors in rat forebrain regions, which may contribute to the distinctive psychopharmacologic profile of asenapine. | 18,719,049 |
Elevated free IGF2 levels in localized, early-stage breast cancer in women. | Epidemiological studies imply an association between circulating IGF1 and breast cancer, whereas the role of IGF2, which also acts on the IGF1 receptor, is less settled. This study investigates the association between IGF2 and breast cancer in patients with localized disease. The participants were women with well-characterized, early stage, localized breast cancer (n=43) and matched healthy women (n=38), from whom fasting serum levels of IGF-related peptides were measured. In patients, mean free IGF2 was increased (+57%, P<0.001), in spite of reduced total IGF2 levels (-12%, P=0.003) when compared with controls. Similar changes were seen in free IGF1 (+28%, P=0.004) and total IGF1 (-16% P=NS). Pro-IGF2 and IGF-binding protein 1 (IGFBP1) were unchanged. IGFBP2 was reduced by 22% in the patients (P=0.004). The patients showed reduced IGFBP3 protease activity and accordingly increased levels of intact IGFBP3, whereas total IGFBP3 was unchanged. Women with localized, early-stage breast cancer show elevated circulating free IGF1 and IGF2, reduced total IGF2 and alterations in IGFBPs. The changes observed despite minimal cancer disease suggest a role for the circulating IGF system in the progression of breast cancer in women. | 18,719,053 |
Urban residence is associated with bronchial hyperresponsiveness in Italian general population samples. | The role of different risk factors for bronchial hyperresponsiveness (BHR), such as gender, atopy, IgE, and environmental factors (smoking, occupational exposure, infections), has been described. Indoor and outdoor pollution play an important role too, but few studies have analyzed the association with BHR. The aim of this study was to assess the effect of urban residence on BHR. We studied two general population samples enrolled in two cross-sectional epidemiological studies performed in Northern Italy (Po Delta, rural area) and Central Italy (Pisa, urban area). We analyzed 2,760 subjects (age range, 8 to 74 years). We performed analysis of variance and logistic regression analysis using ln slope of the dose-response curve of the methacholine challenge test as dependent variable, and sex, age, smoking habits, respiratory symptoms, skin-prick test results, IgE value, residence, and airway caliber as independent variables. The mean value of ln slope of the dose-response curve adjusted for initial airways caliber (by baseline FEV(1) percentage of predicted value) was significantly higher in female subjects, in smokers, in subjects with respiratory symptoms, in younger and older ages, in subjects with high values of IgE, and in subjects with positive skin-prick test results. After controlling for the independent effects of all these variables, living in urban area was an independent risk factor for having BHR (odds ratio, 1.41; 95% confidence interval, 1.13 to 1.76). Living in urban area is a risk factor for increased bronchial responsiveness. | 18,719,062 |
The possible role of hematopoietic cell kinase in the pathophysiology of COPD. | Hematopoietic cell kinase (Hck) is a myeloid cell-specific tyrosine kinase, which is known to induce neutrophil infiltration to the lungs. Although the overexpression of Hck causes emphysema-like histologic changes in mice, its expression and activity in patients with COPD are unclear. The aim of this study was to clarify the expression and activity of Hck in neutrophils from COPD patients, and to investigate the association between the degree of Hck expression and the lung function parameters in COPD patients. Peripheral blood neutrophils were isolated from 22 patients with COPD and 9 healthy subjects (HSs). The protein levels of Hck and phosphorylated Hck were assessed, and the correlation with various background characteristics was evaluated. The Hck protein level was significantly higher in neutrophils from COPD patients compared with HSs (COPD patients, 1.094; HSs, 0.801; p < 0.05). A significant positive correlation was observed between the protein level of Hck and the surface expression of the integrin molecule CD-11b (r = 0.540; p < 0.01) or CXC chemokine receptor-1 (r = 0.432; p < 0.05). In contrast, there was no difference in the phosphorylation of the Hck protein between COPD patients and HSs. The Hck protein level in peripheral blood neutrophils was increased in COPD patients, suggesting that Hck might have an important role in the neutrophil function and play a key role in the pathophysiology of COPD. | 18,719,065 |
Managing reduced methotrexate clearance in a patient with a heterozygous methylenetetrahydrofolate reductase gene polymorphism. | High dose methotrexate has become one of the treatments of choice for patients with primary CNS lymphomas due to its ability to penetrate the blood-brain barrier. A potentially serious complication of this therapy is methotrexate-related nephrotoxicity. We report the case of a patient with a common genetic polymorphism that may have predisposed this patient experience clinically significant toxicity from systemic folate depletion. After the first cycle of chemotherapy that included high dose methotrexate, the patient's serum creatinine rose and the patient's methotrexate level remained above the toxic range for six days. On cycle two, the patient was treated with a 25% dose reduction in methotrexate and more aggressive hydration and alkalization. With this alteration in the regimen, the patient was able to receive six more cycles and had a complete radiographic tumor response in the brain and a disappearance of tumor cells in the CSF without any further renal complications. This case report illustrates the feasibility of administering high dose methotrexate with modifications as a treatment of choice in individuals with methylenetetrahydrofolate reductase gene mutations. | 18,719,070 |
Characterization of the occurrence of ifosfamide-induced neurotoxicity with concomitant aprepitant. | Ifosfamide is metabolized by the cytochrome P450 system to its active form, ifosforamide mustard. A potential side effect is neurotoxicity, often manifesting as confusion, hallucination, or seizure. Aprepitant, a neurokinin-1 inhibitor, is recommended for highly and moderately emetogenic chemotherapy regimens and may interfere with the metabolism of ifosfamide as it inhibits CYP3A4. The objective of the study is to identify if an increase in the incidence of neurotoxicity may be associated with the use of aprepitant with concomitant ifosfamide. A retrospective study of inpatients with sarcoma who received a two or four-day regimen of MAI (mesna, doxorubicin, and ifosfamide) between January 1, 2004 and December 31, 2006 was conducted. Data collection focused on characterizing neurotoxicity of patients receiving ifosfamide with or without aprepitant. Correlation between serum creatinine, albumin, liver function tests, age, gender, and total doses of ifosfamide was examined. A total of 45 patients received ifosfamide of which 23 (51%) were male and 24 (53%) received aprepitant. All baseline characteristics were similar for those who received aprepitant versus those who did not. No significant differences were noted between patients with or without neurotoxicity for age, gender, or liver enzymes. Eight patients (18%) of 45 developed neurotoxicity of which six (75%) of those patients also received aprepitant. A trend of increased occurrence of neurotoxicity was noted with aprepitant administration (6 vs. 2 patients respectively, p = 0.176), although a statistical difference was not observed. A relative risk of 2.6 (95% CI, 0.47-26.6) was associated with the addition of aprepitant. An increased risk was identified for ifosfamide-induced neurotoxicity associated with aprepitant use; however, the observed difference was not statistically significant. The necessity of aprepitant given in association with ifosfamide may need to be reconsidered due to this risk. | 18,719,071 |
Long-term moderate ethanol consumption restores insulin sensitivity in high-fat-fed rats by increasing SLC2A4 (GLUT4) in the adipose tissue by AMP-activated protein kinase activation. | The sole effect of either saturated fatty acid or moderate ethanol consumption on SLC2A4 (GLUT4) expression is widely reported but the combined effects of them remain obscure. Here, we observed their combined effects on SLC2A4 expression, explored the underlying mechanism mediated by AMP-activated protein kinase alpha (PRKAA2) and myocyte enhancer factor 2 (MEF2) both in vivo and in vitro. In the in vivo experiments, 36 male Wistar rats, divided into three groups, were fed with normal diet, high-fat (HF) diet, or HF diet plus ethanol for 22 weeks. We measured the expressions of total-PRKAA2 (T-PRKAA2), phosphorylated-PRKAA2 (pPRKAA2, activated form of PRKAA2), MEF2, and SLC2A4 in epididymal adipose tissues. In the in vitro experiments, primary adipocytes, isolated from normal Wistar rats, were incubated in the presence or absence of palmitate, ethanol, and compound C (an PRKAA2 inhibitor) for 1 h. Thereafter, T-PRKAA2, pPRKAA2, MEF2, and SLC2A4 expressions were measured. We found that both HF diet and in vitro exposition to palmitate impaired SLC2A4 expression in rat adipocytes with a parallel reduction in PRKAA2 activation and MEF2 expression. This impairment was reversed by ethanol administration. We further demonstrated that ethanol-mediated PRKAA2 activation stimulates MEF2 and SLC2A4 expressions in adipocytes, as evidenced by compound C blockade of these effects. In summary, long-term moderate ethanol consumption reversed the adverse effect of saturated fatty acid on SLC2A4 expression in adipocytes, which was likely to be a result of PRKAA2 activation and subsequent up-regulation of MEF2 and SLC2A4 expressions. | 18,719,073 |
Correlation of different circulating endothelial progenitor cells to stages of diabetic retinopathy: first in vivo data. | To investigate vasculogenic circulating progenitor cells (CPCs), endothelial progenitor cells (EPCs), and mature EPCs in patients with type 1 diabetes mellitus (T1DM) with or without diabetic retinopathy (DR). A case-control study comparing 90 patients with T1DM with and without DR was performed. Patients were studied and staged for retinopathy according to the Early Treatment of Diabetic Retinopathy Study (ETDRS) classification. Ninety patients were included: 30 without DR (control [CO]), 30 with mild nonproliferative DR (mNPDR), 10 with moderate-severe NPDR (msNPDR), 10 with mild-moderate proliferative diabetic retinopathy (mmPDR), and 10 with high-risk PDR (hrPDR). CPCs (CD34/CD133), EPCs (CD34/CD133/CD309), and mature EPCs (CD34/CD133/CD309/CD31) were enumerated by flow cytometry. EPCs were reduced in mNPDR (114 +/- 66; P < 0.001) and msNPDR (77 +/- 40; P = 0.042) compared with CO (244 +/- 115). In contrast, EPCs were unchanged in mmPDR (248 +/- 155) compared with CO. Strikingly, EPCs were augmented in hrPDR (389 +/- 124) compared with all other stages. Numbers of undifferentiated progenitor cells (CPCs) did not differ among CO, mmPDR, and hrPDR. Augmentation (3x) of mature EPCs in hrPDR (325 +/- 118; P < 0.001) compared with CO (100 +/- 49) but against all other stages of DR was observed. The percentage of mature EPCs/EPCs was augmented in an ETDRS classification-dependent manner. In patients with T1DM with DR, EPCs undergo stage-related regulation. In nonproliferative retinopathy, a reduction of EPCs was observed, and in proliferative retinopathy, a dramatic increase of mature EPCs was observed. | 18,719,083 |
Visual and cognitive deficits predict stopping or restricting driving: the Salisbury Eye Evaluation Driving Study (SEEDS). | To determine the visual and other factors that predict stopping or restricting driving in older drivers. A group of 1425 licensed drivers aged 67 to 87 years, who were residents of greater Salisbury, participated. At 1 year after enrollment, this group was categorized into those who had stopped driving, drove only within their neighborhood, or continued to drive beyond their neighborhood. At baseline, a battery of structured questionnaires, vision, and cognitive tests were administered. Multivariate analysis determined the factors predictive of stopping or restricting driving 12 months later. Of the 1425 enrolled, 1237 (87%) were followed up at 1 year. Excluding those who were already limiting their driving at baseline (n = 35), 1.5% (18/1202) had stopped and 3.4% (41/1202) had restricted their driving. The women (odds ratio [OR], 4.01; 95% confidence interval [CI], 2.05-8.20) and those who prefer to be driven (OR, 3.91; 95% CI, 1.91-8.00) were more likely to stop or restrict driving. Depressive symptoms increased likelihood of restricting or stopping driving (OR, 1.08; 95% CI, 1.009-1.16 per point Geriatric Depression Scale). Slow visual scanning and psychomotor speed (Trail Making Test, Part A: OR, 1.02; 95% CI, 1.01-1.03), poor visuoconstructional skills (Beery-Buktenica Test of Visual Motor Integration: OR, 1.14; 95% CI, 1.05-1.25), and reduced contrast sensitivity (OR, 1.15; 95% CI, 1.03-1.28) predicted stopping or reducing driving. Visual field loss and visual attention were not associated. The effect of vision on changing driving behavior was partially mediated by cognition, depression, and baseline driving preferences. In this cohort, contrast sensitivity and cognitive function were independently associated with incident cessation or restriction of driving space. These data suggest drivers with functional deficits make difficult decisions to restrict or stop driving. | 18,719,088 |
TRPV4 channel participates in receptor-operated calcium entry and ciliary beat frequency regulation in mouse airway epithelial cells. | The rate of mucociliary clearance in the airways is a function of ciliary beat frequency (CBF), and this, in turn, is increased by increases in intracellular calcium. The TRPV4 cation channel mediates Ca(2+) influx in response to mechanical and osmotic stimuli in ciliated epithelia. With the use of a TRPV4-deficient mouse, we now show that TRPV4 is involved in the airways' response to physiologically relevant physical and chemical stimuli. Ciliary TRPV4 expression in tracheal epithelial cells was confirmed with immunofluorescence in TRPV4(+/+) mice. Ciliated tracheal cells from TRPV4(-/-) mice showed no increases in intracellular Ca(2+) and CBF in response to the synthetic activator 4alpha-phorbol 12,13-didecanoate (4alphaPDD) and reduced responses to mild temperature, another TRPV4-activating stimulus. Autoregulation of CBF in response to high viscosity solutions is preserved in TRPV4(-/-) despite a reduced Ca(2+) signal. More interestingly, TRPV4 contributed to an ATP-induced increase in CBF, providing a pathway for receptor-operated Ca(2+) entry but not store-operated Ca(2+) entry as the former mechanism is lost in TRPV4(-/-) cells. Collectively, these results suggest that TRPV4 is predominantly located in the cilia of tracheal epithelial cells and plays a key role in the transduction of physical and chemical stimuli into a Ca(2+) signal that regulates CBF and mucociliary transport. Moreover, these studies implicate the participation of TRPV4 in receptor-operated Ca(2+) entry. | 18,719,094 |
Endogenous oxidative stress produces diversity and adaptability in biofilm communities. | Many bacterial species are capable of biofilm growth, in which cells live and replicate within multicellular community groups. Recent work shows that biofilm growth by a wide variety of bacterial species can generate genetic diversity in microbial populations. This finding is significant because the presence of diverse subpopulations can extend the range of conditions in which communities can thrive. Here, we used biofilms formed by the pathogen Pseudomonas aeruginosa to investigate how this population diversity is produced. We found that some cells within biofilms incur double-stranded DNA breaks caused by endogenous oxidative stress. Genetic variants then result when breaks are repaired by a mutagenic mechanism involving recombinatorial DNA repair genes. We hypothesized that the mutations produced could promote the adaptation of biofilm communities to changing conditions in addition to generating diversity. To test this idea, we exposed biofilms to an antibiotic and found that the oxidative stress-break repair mechanism increased the emergence of antibiotic-resistant bacteria. The diversity and adaptability produced by this mechanism could help biofilm communities survive in harsh environments. | 18,719,125 |
Dissecting the roles of MuB in Mu transposition: ATP regulation of DNA binding is not essential for target delivery. | Collaboration between MuA transposase and its activator protein, MuB, is essential for properly regulated transposition. MuB activates MuA catalytic activity, selects target DNA, and stimulates transposition into the selected target site. Selection of appropriate target DNA requires ATP hydrolysis by the MuB ATPase. By fusing MuB to a site-specific DNA-binding protein, the Arc repressor, we generated a MuB variant that could select target DNA independently of ATP. This Arc-MuB fusion protein allowed us to test whether ATP binding and hydrolysis by MuB are necessary for stimulation of transposition into selected DNA, a process termed target delivery. We find that with the fusion proteins, MuB-dependent target delivery occurs efficiently under conditions where ATP hydrolysis is prevented by mutation or use of ADP. In contrast, no delivery was detected in the absence of nucleotide. These data indicate that the ATP- and MuA-regulated DNA-binding activity of MuB is not essential for target delivery but that activation of MuA by MuB strictly requires nucleotide-bound MuB. Furthermore, we find that the fusion protein directs transposition to regions of the DNA within 40-750 bp of its own binding site. Taken together, these results suggest that target delivery by MuB occurs as a consequence of the ability of MuB to stimulate MuA while simultaneously tethering MuA to a selected target DNA. This tethered-activator model provides an attractive explanation for other examples of protein-stimulated control of target site selection. | 18,719,126 |
Use of sirolimus (rapamycin) to treat refractory Crohn's disease. | We present the case of a 37-year-old woman with severe refractory colonic and perianal Crohn's disease who had lost response to second-line, steroid-sparing treatments azathioprine, methotrexate and infliximab. For many such patients extensive surgery has often been considered the only option. New insights provided by the results of genome-wide association scanning in Crohn's disease highlight autophagy, a cellular process implicated in the clearance of intracellular bacteria, as a key process in Crohn's disease pathogeneses. Sirolimus (rapamycin) is a drug used to upregulate autophagy in cell culture in the laboratory, and in clinical practice to prevent rejection following organ transplantation due to independent immunosuppressive action. Our patient was treated with sirolimus for 6 months at a dose that maintained serum trough levels of 5 ng/ml. There was marked and sustained improvement in Crohn's disease symptoms with the Harvey-Bradshaw index falling from 13 to 3, in serum markers of inflammation (C-reactive protein fell from 79 to 2) and endoscopic appearance. This is the first reported case of the use of sirolimus to treat Crohn's disease. | 18,719,139 |
Influence of automated screening and confirmation of extended-spectrum beta-lactamase-producing members of the Enterobacteriaceae on prescribing of antibiotics. | This study investigated the clinician response to the extended-spectrum beta-lactamase (ESBL) confirmation report generated by an automated detection system, MicroScan Walkaway. The study compared two cohorts (pre- and post-automated detection) of patients with an ESBL-producing Escherichia coli or Klebsiella species non-urinary infection over the period October 2001-December 2006. Acceptance of the report, as defined by the initiation of carbapenem therapy, was observed in 69.2% of the post-automated detection cohort (n=78) versus 20% in the pre-automated detection period (n=15) (P<or=0.001). The utilization of a carbapenem increased progressively over the course of the study. Moreover, the time to initiation of carbapenem therapy was reduced from 15.7+/-4.9 to 0.1+/-2.0 days (P<or=0.001) after implementation of this automated detection system. Overall, clinicians responded positively to the ESBL automated detection report, as gauged by the increased utilization of a carbapenem and the earlier initiation of appropriate therapy; however, reductions in length of stay and mortality were not observed in this infected population. | 18,719,186 |
A new inflammatory cytokine on the block: re-thinking periodontal disease and the Th1/Th2 paradigm in the context of Th17 cells and IL-17. | For almost two decades, the Th1/Th2 paradigm has offered a productive conceptual framework for investigating the pathogenesis of periodontitis. However, as with many other inflammatory diseases, the observed role of T-cell-mediated immunity in periodontitis did not readily fit this model. A new subset of CD4+ T-cells was recently discovered that explains many of the discrepancies in the classic Th1/Th2 model, and has been termed "Th17" based on its secretion of the novel pro-inflammatory cytokine IL-17. The identification of Th17 cells as a novel effector T-cell population compels re-examination of periodontitis in the context of the new subset and its signature cytokines. This review aims to offer a clarifying insight into periodontal pathogenesis under the extended Th1/Th2/Th17 paradigm, and is predicated on the principle that periodontal disease activity is determined by a complex interplay between the immune system and periodontal pathogens. The re-examination of existing periodontal literature and further studies in the light of these new discoveries may help explain how the inflammatory response results in damage to the periodontium while generally failing to control the pathogens. This knowledge is essential for the development of immunomodulatory intervention strategies for fine-tuning the host response to maximize the protective and minimize the destructive aspects of the periodontal host response. Moreover, with the advent of anti-cytokine biologic drugs that target the Th1 and Th17 pathways in autoimmunity, the potential consequences to periodontal disease susceptibility in humans need to be understood. | 18,719,207 |
Aging affects vascular structure and function in a limb-specific manner. | The limb-specific effects of aging upon vessel structure and function are not well understood. Consequently, in 12 young (26 +/- 2 yr) and 12 old (72 +/- 1 yr) healthy subjects, we utilized ultrasound Doppler to evaluate intima-media thickness (IMT), ischemic reperfusion, and flow-mediated dilation (FMD) following (5 min) suprasystolic cuff occlusion in both the arm [brachial artery (BA)] and the leg [popliteal artery (PA)]. Structural measurements, whether normalized for vessel size or not, revealed a greater IMT in both the BA and PA with age (young: BA 0.028 +/- 0.001 and PA 0.046 +/- 0.003 cm, old: BA 0.039 +/- 0.002 and PA 0.073 +/- 0.005 cm; P < 0.05). Ischemic reperfusion revealed a similar pattern as IMT in terms of limb and age-related differences. There was an age-related attenuation in both BA FMD (old: 38% smaller BA FMD compared with young) and PA FMD (old: 71% smaller PA FMD compared with young). However, when this percent change was normalized for shear rate, only the PA FMD of the old group was still significantly attenuated (old: 41% smaller PA FMD/shear rate compared with young). Together, the finding of differential structural and functional parameters in the arms and legs of healthy young people, and the somewhat negative findings that are specific to the legs of otherwise healthy older people (greater IMT and attenuated FMD), support and may help to better understand the increased propensity to develop a vascular pathology in the legs with age. | 18,719,234 |
3D 3He diffusion MRI as a local in vivo morphometric tool to evaluate emphysematous rat lungs. | In this work, we investigate (3)He magnetic resonance imaging as a noninvasive morphometric tool to assess emphysematous disease state on a local level. Emphysema was induced intratracheally in rats with 25 U/100 g body wt of porcine pancreatic elastase dissolved in 200 microl saline. Rats were then paired with saline-dosed controls. Nine three-dimensional (3D) (3)He diffusion-weighted images were acquired at 1, 2, or 3 wk postdose, after which the lungs were harvested and prepared for histological analysis. Recently introduced indexes sensitive to the heterogeneity of the air space size distribution were calculated. These indexes, D(1) and D(2), were derived from the moments of the mean equivalent airway diameters. Averaged over the entire lung, it is shown that the average (3)He diffusivity (D(ave)) correlates well with histology (R = 0.85, P < 0.0001). By matching small (0.046 cm(2)) regions in (3)He images with corresponding regions in histological slices, D(ave) correlates significantly with both D(1) and D(2) (R = 0.88 and R = 0.90, respectively, with P < 0.0001). It is concluded that (3)He MRI is a viable noninvasive morphometric tool for localized in vivo emphysema assessment. | 18,719,237 |
tRNA cleavage is a conserved response to oxidative stress in eukaryotes. | Recent results have identified a diversity of small RNAs in a wide range of organisms. In this work, we demonstrate that Saccharomyces cerevisiae contains a small RNA population consisting primarily of tRNA halves and rRNA fragments. Both 5' and 3' fragments of tRNAs are detectable by Northern blot analysis, suggesting a process of endonucleolytic cleavage. tRNA and rRNA fragment production in yeast is most pronounced during oxidative stress conditions, especially during entry into stationary phase. Similar tRNA fragments are also observed in human cell lines and in plants during oxidative stress. These results demonstrate that tRNA cleavage is a conserved aspect of the response to oxidative stress. | 18,719,243 |
Coupled superconducting and magnetic order in CeCoIn5. | Strong magnetic fluctuations can provide a coupling mechanism for electrons that leads to unconventional superconductivity. Magnetic order and superconductivity have been found to coexist in a number of magnetically mediated superconductors, but these order parameters generally compete. We report that close to the upper critical field, CeCoIn5 adopts a multicomponent ground state that simultaneously carries cooperating magnetic and superconducting orders. Suppressing superconductivity in a first-order transition at the upper critical field leads to the simultaneous collapse of the magnetic order, showing that superconductivity is necessary for the magnetic order. A symmetry analysis of the coupling between the magnetic order and the superconducting gap function suggests a form of superconductivity that is associated with a nonvanishing momentum. | 18,719,250 |
High-quality binary protein interaction map of the yeast interactome network. | Current yeast interactome network maps contain several hundred molecular complexes with limited and somewhat controversial representation of direct binary interactions. We carried out a comparative quality assessment of current yeast interactome data sets, demonstrating that high-throughput yeast two-hybrid (Y2H) screening provides high-quality binary interaction information. Because a large fraction of the yeast binary interactome remains to be mapped, we developed an empirically controlled mapping framework to produce a "second-generation" high-quality, high-throughput Y2H data set covering approximately 20% of all yeast binary interactions. Both Y2H and affinity purification followed by mass spectrometry (AP/MS) data are of equally high quality but of a fundamentally different and complementary nature, resulting in networks with different topological and biological properties. Compared to co-complex interactome models, this binary map is enriched for transient signaling interactions and intercomplex connections with a highly significant clustering between essential proteins. Rather than correlating with essentiality, protein connectivity correlates with genetic pleiotropy. | 18,719,252 |
Star formation around supermassive black holes. | The presence of young massive stars orbiting on eccentric rings within a few tenths of a parsec of the supermassive black hole in the galactic center is challenging for theories of star formation. The high tidal shear from the black hole should tear apart the molecular clouds that form stars elsewhere in the Galaxy, and transport of stars to the galactic center also appears unlikely during their lifetimes. We conducted numerical simulations of the infall of a giant molecular cloud that interacts with the black hole. The transfer of energy during closest approach allows part of the cloud to become bound to the black hole, forming an eccentric disk that quickly fragments to form stars. Compressional heating due to the black hole raises the temperature of the gas up to several hundred to several thousand kelvin, ensuring that the fragmentation produces relatively high stellar masses. These stars retain the eccentricity of the disk and, for a sufficiently massive initial cloud, produce an extremely top-heavy distribution of stellar masses. This potentially repetitive process may explain the presence of multiple eccentric rings of young stars in the presence of a supermassive black hole. | 18,719,276 |
Immunosuppression induced by a conditioned stimulus associated with cocaine self-administration. | Cocaine addiction is known to impair immune system function, but the effects of repeated treatment with cocaine in a self-administration model, its withdrawal as well as reinstatement of cocaine-seeking behavior on cell-mediated immunity are not well known. Cocaine self-administered for 18 days induced a significant increase in spleen weight, plasma corticosterone levels, interleukin (IL)-10, and tumor necrosis factor-alpha production, while concanavalin A-stimulated proliferation responses of peripheral blood T-lymphocytes and interferon-gamma production by splenic lymphocytes were not altered. After 10 days withdrawal from cocaine, reinstatement of cocaine seeking behavior induced either by a priming dose of the drug (unconditioned stimulus), by cue previously associated with cocaine self-administration (conditioned stimuli), or by both these stimuli evoked similar changes in several immunological parameters, for example, a decrease in relative spleen weight, proliferative activity of splenocytes, and their ability to produce IL-10. The results showed that the cue previously associated with cocaine suppressed some parameters of cell-mediated immunity to the same degree as re-exposure to cocaine. The present study provides the first evidence that alterations of immune status can be conditioned by environmental stimuli paired with cocaine administration. | 18,719,314 |
Diazepam protects against the enhanced toxicity of cocaine adulterated with atropine. | We examined the toxicity of cocatropine (cocaine/atropine mixture) and the therapeutic potential of diazepam on some behavioral and physiological parameters in rats. Atropine (20 and 60 mg/kg) or cocaine (40 mg/kg) alone did not induce any seizure or death, but the combination significantly increased both, after both acute and binge treatment. There was a significant increase of EEG mean total spectral power in cocatropine- in comparison with cocaine-treated animals. Hyperlocomotion was observed in non-seizuring rats treated with cocaine or cocatropine. Cocaine, atropine 60, and cocatropine (40 + 20 and 40 + 60) all induced hyperthermic effects in non-seizuring rats, while cocatropine (40 + 60)-seizuring animals had hypothermia. An initial hypertensive and tachycardiac effect within 15 min was followed by a secondary fall in the cocatropine (40 + 60) group. Cocatropine toxicity was partially or fully reversed by diazepam (5 mg/kg), given intraperitoneally after the first seizure. The present findings provide, for the first time, details of a synergistic toxic effect of the cocaine/atropine mixture and of the potential of diazepam for treating cocatropine-related hospital emergencies. | 18,719,317 |
Acute basilar artery occlusion in a patient with left subclavian artery occlusion due to first rib anomaly: case report. | A previously healthy 22-year-old man presented with thoracic outlet syndrome manifesting as Raynaud's phenomenon in the left hand and embolic occlusion of the basilar artery. Three-dimensional computed tomography angiography showed that the left subclavian artery was occluded as it passed over the abnormal first rib. Retrograde propagation of the thrombus from the site of arterial occlusion and/or reflux of embolic material was suspected. Medical therapy was started. The patient underwent resection of the anomalous rib. Postoperative angiography demonstrated that the subclavian artery was recanalized with almost normal distal flow. The basilar artery was also recanalized. Thoracic outlet syndrome due to a first rib anomaly may cause stroke. | 18,719,326 |
Low prevalence of metabolic syndrome and its components in rural Japan. | Tsunan, Niigata is a non-westernized rural Japanese town, known for heavy snowfalls and as a rice-producing area, whose inhabitants have a long life expectancy. We investigated the prevalence of obesity, metabolic syndrome (MetS) and its components in Tsunan. A total of 1,155 men and women, 40-69 years of age were recruited from participants in the 2005 public-health program in Tsunan. Obesity was defined as body-mass index (BMI) >or= 25 kg/m(2). MetS was defined as BMI >or= 25 kg/m(2) as well as at least two of the following three items: (1) high glycosylated hemoglobin (HbA1c >or= 5.5%); (2) high blood pressure (HBP: systolic blood pressure >or= 130 mmHg or diastolic blood pressure >or= 85 mmHg), and (3) low high-density lipoprotein cholesterol (HDL-C < 40 mg/dL). If an individual was diagnosed with diabetes, hypertension, or dyslipidemia, each item was recorded as a positive finding. The prevalence of MetS and its components among Tsunan inhabitants were compared to the results of the 2005 Japanese nationwide survey. The prevalence of MetS was 4.6% in males and 4.2% in females. The prevalence of obesity, high HbA1c, HBP, and low HDL-C were 22.1/22.2%, 13.4/16.4%, 46.6/40.0%, and 9.2/3.9% in males/females, respectively. All values were significantly lower than the national results, except for the rate of female obesity. The lower prevalence of MetS and its components in Tsunan may be due to the consumption of traditional Japanese food, which is still commonly eaten there, and the higher levels of regular physical activity of farmers. | 18,719,340 |
A novel human BTB-kelch protein KLHL31, strongly expressed in muscle and heart, inhibits transcriptional activities of TRE and SRE. | The Bric-a-brac, Tramtrack, Broad-complex (BTB) domain is a protein-protein interaction domain that is found in many zinc finger transcription factors. BTB containing proteins play important roles in a variety of cellular functions including regulation of transcription, regulation of the cytoskeleton, protein ubiquitination, angiogenesis, and apoptosis. Here, we report the cloning and characterization of a novel human gene, KLHL31, from a human embryonic heart cDNA library. The cDNA of KLHL31 is 5743 bp long, encoding a protein product of 634 amino acids containing a BTB domain. The protein is highly conserved across different species. Western blot analysis indicates that the KLHL31 protein is abundantly expressed in both embryonic skeletal and heart tissue. In COS-7 cells, KLHL31 proteins are localized to both the nucleus and the cytoplasm. In primary cultures of nascent mouse cardiomyocytes, the majority of endogenous KLHL31 proteins are localized to the cytoplasm. KLHL31 acts as a transcription repressor when fused to GAL4 DNA-binding domain and deletion analysis indicates that the BTB domain is the main region responsible for this repression. Overexpression of KLHL31 in COS-7 cells inhibits the transcriptional activities of both the TPA-response element (TRE) and serum response element (SRE). KLHL31 also significantly reduces JNK activation leading to decreased phosphorylation and protein levels of the JNK target c-Jun in both COS-7 and Hela cells. These results suggest that KLHL31 protein may act as a new transcriptional repressor in MAPK/JNK signaling pathway to regulate cellular functions. | 18,719,355 |
Dissecting autophagosome formation: the missing pieces. | The formation of autophagosomes is the central part of the macroautophagy pathway. Little is known, however, about how the participants in this process affect the membrane dynamics at the phagophore assembly site (PAS). Recently, we demonstrated that Atg8, a lipid-conjugated ubiquitin-like protein, controls the expansion of the phagophore. In addition, we showed that the autophagosome formation process can be traced and dissected by time-lapse fluorescence microscopy observation of GFP-Atg8. These findings constitute one step further in our understanding of autophagosome formation. Key questions remain open, however, on how the actions of other proteins at the PAS are coordinated with that of Atg8 and on the precise role of Atg8. | 18,719,358 |
The metastasis-associated gene MTA1 is upregulated in advanced ovarian cancer, represses ERbeta, and enhances expression of oncogenic cytokine GRO. | The metastasis-associated genes MTA1 and MTA3 are transcriptional repressors with potential effects on cancer. We analyzed the expression of MTA1, MTA3, ERalpha, ERbeta and E-cadherin in a total of 115 paraffin-embedded ovarian cancer tissues with respect to cancer staging and FIGO grading. Expression of MTA1, but not that of MTA3, was found to be significantly enhanced in ovarian cancer tissues with advanced cancer stages and higher FIGO grading, indicating an important role of MTA1 in the progression of ovarian cancer. To get further insights into the function of MTA1 in ovarian cancer, MTA1-overexpressing cancer cell clones were generated. In vitro, overexpression of exogenous MTA1 in OVCAR-3 cells had no effect on cell proliferation but enhanced the ability of anchorage-independent growth in soft agar colony formation assays. MTA1 overexpression resulted in downregulation of E-cadherin and MTA3 expression and enhanced expression of the transcriptional repressors SNAIL and SLUG. MTA1 further reduced ERbeta expression in vitro and inversely correlated with ERbeta expression in vivo. Screening for the expression of angiogenic cytokines expressed by ovarian cancer cells revealed MTA1-mediated upregulation of the oncogenic and angiogenic cytokine GRO (growth-regulated oncogene, CXCL1). Thus, in ovarian cancer, MTA1 expression directly and indirectly regulates the expression of several cancer-promoting as well as metastasis-facilitating factors, indicating an important role for MTA1 expression during ovarian cancer progression. | 18,719,363 |
Platinums sensitize human epithelial tumor cells to lymphotoxin alpha by inhibiting NFkappaB-dependent transcription. | Lymphotoxin alpha (LTalpha) was first identified as a direct anti-tumor factor, whereas increasing evidence has recently shown that in most cases the growth inhibition mediated by LTalpha requires the synergistic action of other factors, such as RNA transcription or protein synthesis inhibitor. In this study, we evaluated the combined effects of LTalpha and ten chemotherapeutic drugs on cell growth in a panel of human epithelial tumor cells, and explored the molecular mechanism of their mutual action. The results showed that platinums (cisplatin, carboplatin, oxaliplatin) are more universally effective than other chemotherapeutic drugs (doxorubicin, epi-doxorubicin, 5-flourouracil, mitomycin, cyclophosphamide, vincristine and vinorelbine) to enhance the response of six human epithelial tumor cell lines (A375, Bcap37, NCI-H157, SW480, BGC-823 and HeLa) to LTalpha. A systemic treatment with a combination of LTalpha and cisplatin in a human Bcap37 breast cancer xenograft nude mice model dramatically improved the therapeutic efficacy of LTalpha. Further analysis revealed that the sensitization of platinums was associated with platinums-induced suppression of nuclear factor-kappaB (NFkappaB) and subsequent downregulation of X-linked inhibitor of apoptosis protein (XIAP), which rescued caspase-3 from inhibition. Our results suggested that a proper combination of bio-agents such as LTalpha and conventional chemotherapeutic drugs such as platinums may be an efficient treatment strategy for human epithelial cancers. | 18,719,365 |
Modulation of the "blood-tumor" barrier improves immunotherapy. | Blood vessels inside tumors are crucial for cancer survival and progression but equally contribute to the tumor's intrinsic resistance to therapy. Abnormal blood flow in the local tumor environment acts as a physiological barrier to the delivery of chemotherapeutic agents. Furthermore, tumor vasculature can also act as a barrier for immune cell migration into the tumor parenchyma. Much has been made of anti-angiogenic therapies that specifically inhibit vessel growth. However, recent findings demonstrate that the chaotic architecture of tumor blood vessels can be reversed which in turn normalizes blood flow and physical parameters in the tumor environment. Importantly, vessel normalization also improves lymphocyte migration into tumor tissue and immune destruction. Identification of regulator of G protein signaling 5 (RGS5) as a key modulator of the vascular barrier in tumor progression and regression has brought new insights into the molecular basis of vessel normalization and opens new therapeutic opportunities. | 18,719,382 |
RecQ family helicases in genome stability: lessons from gene disruption studies in DT40 cells. | Cells of all living organisms have evolved complex mechanisms to maintain genome stability. There is increasing evidence that spontaneous genomic instability occurs primarily during DNA replication. RecQ DNA helicases function during DNA replication and are essential for the maintenance of genome stability. In human cells, there exist five RecQ DNA helicases, and mutations of three of these helicases, encoded by the BLM, WRN and RECQL4 genes, give rise to the cancer predisposition disorders, Bloom syndrome (BS), Werner syndrome (WS) and Rothmund-Thomson syndrome (RTS), respectively. Individuals suffering from WS and RTS also show premature aging phenotypes. Although the two remaining helicases, RECQL1 and RECQL5, have not yet been associated with heritable human diseases, a single nucleotide polymorphism of RECQL1 is associated with reduced survival of pancreatic cancer, and RecQl5 knockout mice show a predisposition to cancer. Here, we review the functions of eukaryotic RecQ helicases, focusing primarily on BLM in the maintenance of genome stability through various pathways of nucleic acid metabolism and with special reference to DNA replication. | 18,719,387 |
Motor and somatosensory evoked potentials are well maintained in patients given dexmedetomidine during spine surgery. | Many commonly used anesthetic agents produce a dose-dependent amplitude reduction and latency prolongation of evoked responses, which may impair diagnosis of intraoperative spinal cord injury. Dexmedetomidine is increasingly used as an adjunct for general anesthesia. Therefore, the authors tested the hypothesis that dexmedetomidine does not have a clinically important effect on somatosensory and transcranial motor evoked responses. Thirty-seven patients were enrolled and underwent spinal surgery with instrumentation during desflurane and remifentanil anesthesia with dexmedetomidine as an anesthetic adjunct. Upper- and lower-extremity transcranial motor evoked potentials and somatosensory evoked potentials were recorded during four defined periods: baseline without dexmedetomidine; two periods with dexmedetomidine (0.3 and 0.6 ng/ml), in a randomly determined order; and a final period 1 h after drug discontinuation. The primary outcomes were amplitude and latency of P37/N20, and amplitude, area under the curve, and voltage threshold for transcranial motor evoked potential stimulation. Of the total, data from 30 patients were evaluated. Use of dexmedetomidine, as an anesthetic adjunct, did not have an effect on the latency or amplitude of sensory evoked potentials greater than was prespecified as clinically relevant, and though the authors were unable to claim equivalence on the amplitude of transcranial motor evoked responses due to variability, recordings were made throughout the study in all patients. Use of dexmedetomidine as an anesthetic adjunct at target plasma concentrations up to 0.6 ng/ml does not change somatosensory or motor evoked potential responses during complex spine surgery by any clinically significant amount. | 18,719,439 |
Perineural administration of dexmedetomidine in combination with bupivacaine enhances sensory and motor blockade in sciatic nerve block without inducing neurotoxicity in rat. | The current study was designed to test the hypothesis that high-dose dexmedetomidine added to local anesthetic would increase the duration of sensory and motor blockade in a rat model of sciatic nerve blockade without causing nerve damage. Thirty-one adult Sprague-Dawley rats received bilateral sciatic nerve blocks with either 0.2 ml bupivacaine, 0.5%, and 0.5% bupivacaine plus 0.005% dexmedetomidine in the contralateral extremity, or 0.2 ml dexmedetomidine, 0.005%, and normal saline in the contralateral extremity. Sensory and motor function were assessed by a blinded investigator every 30 min until the return of normal sensory and motor function. Sciatic nerves were harvested at either 24 h or 14 days after injection and analyzed for perineural inflammation and nerve damage. High-dose dexmedetomidine added to bupivacaine significantly enhanced the duration of sensory and motor blockade. Dexmedetomidine alone did not cause significant motor or sensory block. All of the nerves analyzed had normal axons and myelin at 24 h and 14 days. Bupivacaine plus dexmedetomidine showed less perineural inflammation at 24 h than the bupivacaine group when compared with the saline control. The finding that high-dose dexmedetomidine can safely improve the duration of bupivacaine-induced antinociception after sciatic nerve blockade in rats is an essential first step encouraging future studies in humans. The dose of dexmedetomidine used in this study may exceed the sedative safety threshold in humans and could cause prolonged motor blockade; therefore, future work with clinically relevant doses is necessary. | 18,719,449 |
A118G single nucleotide polymorphism of human mu-opioid receptor gene influences pain perception and patient-controlled intravenous morphine consumption after intrathecal morphine for postcesarean analgesia. | Previous studies have shown that genetic variability at position 118 of the human mu-opioid receptor gene altered patients' response to intravenous morphine. The purpose of this study was to investigate whether this polymorphism contributes to the variability in response to morphine for postcesarean analgesia. After investigators obtained informed consent, 588 healthy women received 0.1 mg intrathecal morphine for postcesarean analgesia. Their blood samples were genotyped for the A118G polymorphism-A118 homozygous (AA), heterozygous (AG), or homozygous for the G allele (GG). Pain scores, the severity of nausea and vomiting, the incidence of pruritus, and the total self-administered intravenous morphine were recorded for the first 24 postoperative hours. Two hundred seventy women (46%) were AA, 234 (40%) were AG, and 82 (14%) were GG. The 24-h self-administered intravenous morphine consumption was lowest in the AA group (P = 0.001; mean, 5.9; 95% confidence interval, 5.1-6.8) versus the AG (8.0; 6.9-9.1) and GG groups (9.4; 7.3-11.5). Pain scores were lowest in the AA group and highest in the GG group, with a statistically significant difference detected between AA, AG, and GG (P = 0.049). Total morphine consumption was also influenced by patients' age and paying status. AA group was associated with the highest incidence of nausea (26 of 272 [9.6%]; P = 0.02) versus the other two groups (13 of 234 [5.6%] and 1 of 82 [1.2%] for AG and GG, respectively). Genetic variation at position 118 of the mu-opioid receptor is associated with interindividual differences in pain scores, self-administered intravenous morphine, and the incidence of nausea postoperatively. | 18,719,451 |
Heterogeneous chemistry in the atmosphere of Mars. | Hydrogen radicals are produced in the martian atmosphere by the photolysis of water vapour and subsequently initiate catalytic cycles that recycle carbon dioxide from its photolysis product carbon monoxide. These processes provide a qualitative explanation for the stability of the atmosphere of Mars, which contains 95 per cent carbon dioxide. Balancing carbon dioxide production and loss based on our current understanding of the gas-phase chemistry in the martian atmosphere has, however, proven to be difficult. Interactions between gaseous chemical species and ice cloud particles have been shown to be key factors in the loss of polar ozone observed in the Earth's stratosphere, and may significantly perturb the chemistry of the Earth's upper troposphere. Water-ice clouds are also commonly observed in the atmosphere of Mars and it has been suggested previously that heterogeneous chemistry could have an important impact on the composition of the martian atmosphere. Here we use a state-of-the-art general circulation model together with new observations of the martian ozone layer to show that model simulations that include chemical reactions occurring on ice clouds lead to much improved quantitative agreement with observed martian ozone levels in comparison with model simulations based on gas-phase chemistry alone. Ozone is readily destroyed by hydrogen radicals and is therefore a sensitive tracer of the chemistry that regulates the atmosphere of Mars. Our results suggest that heterogeneous chemistry on ice clouds plays an important role in controlling the stability and composition of the martian atmosphere. | 18,719,584 |
A T-cell-specific CD154 transcriptional enhancer located just upstream of the promoter. | CD154 (CD40-ligand) is a critical immune regulator. CD154 expression is tightly regulated and largely restricted to activated CD4 T cells. Using DNase I hypersensitivity site (HSS) mapping, we identified two novel HSS mapping to the human CD154 promoter element and just upstream. Both HSS were activation independent and CD4 T-cell specific. Approximately 350 bp of DNA sequence flanking the upstream HSS site was highly conserved between mouse and man, and was rich in binding sites for GATA and NFAT proteins. Gel shift and chromatin immunoprecipitation assays demonstrated both NFAT1 and the Th2 factor, GATA-3, bound this enhancer element in vitro and in vivo, respectively. A PstI/XbaI 345 bp fragment of this region acted as a transcriptional enhancer of the CD154 promoter in primary human CD4 T cells. Overexpression of repressor of GATA and a dominant negative GATA-3 protein independently inhibited transcription, whereas overexpression of wild-type GATA-3 enhanced transcriptional activity, by this element in primary CD4 T cells. Moreover, more interleukin-4-producing CD4 T cells expressed CD154 following activation than interferon-gamma-producing CD4 T cells. Thus, we identified a novel T-cell-specific, GATA-3 responsive, CD154 transcriptional enhancer, which may contribute to increased propensity of Th2 cells to express CD154. | 18,719,603 |
Lysogenic virus-host interactions predominate at deep-sea diffuse-flow hydrothermal vents. | The consequences of viral infection within microbial communities are dependent on the nature of the viral life cycle. Among the possible outcomes is the substantial influence of temperate viruses on the phenotypes of lysogenic prokaryotes through various forms of genetic exchange. To date, no marine microbial ecosystem has consistently shown a predisposition for containing significant numbers of inducible temperate viruses. Here, we show that deep-sea diffuse-flow hydrothermal vent waters display a consistently high incidence of lysogenic hosts and harbor substantial populations of temperate viruses. Genetic fingerprinting and initial metagenomic analyses indicate that temperate viruses in vent waters appear to be a less diverse subset of the larger virioplankton community and that these viral populations contain an extraordinarily high frequency of novel genes. Thus, it appears likely that temperate viruses are key players in the ecology of prokaryotes within the extreme geothermal ecosystems of the deep sea. | 18,719,614 |
Adiposity measures and oxidative stress among police officers. | Our objective was to investigate associations between adiposity measures (BMI, waist circumference, waist-to-hip ratio, waist-to-height ratio, and abdominal height) and biomarkers of oxidative stress (glutathione (GSH), GSH peroxidase (GSH-Px), vitamin C, thiobarbituric acid reactive substances (TBARS), and trolox equivalent antioxidant capacity (TEAC)) among police officers. This cross-sectional study included randomly selected police officers (43 policewomen; 67 policemen) from Buffalo, New York. Adiposity measures were performed using standardized methods. Biomarkers were measured on fasting blood specimens. An oxidative stress score (OSS) was created as a composite of the biomarkers. ANOVAs were used to compare mean levels of biomarkers across tertiles of the adiposity measures. Officers were 26- to 61-years old. GSH was inversely associated with waist circumference (trend P = 0.030) and waist-to-hip ratio (trend P = 0.026). GSH-Px was inversely associated with BMI (trend P = 0.004) and with waist-to-height ratio (trend P = 0.017). No associations were observed for TEAC, TBARS, or OSS with any adiposity measure. Significant interactions were observed by physical activity status for GSH with waist circumference and waist-to-hip ratio and for vitamin C with waist circumference, waist-to-hip and waist-to-height ratios. The above associations were inversely related only among officers who reported engaging in physical activity. Inverse associations were observed for BMI and waist circumference with GSH, but only among women; the interaction with gender was significant. Larger indices of adiposity were associated with increased levels of oxidative stress and decreased levels of antioxidant defense. | 18,719,659 |
Role of estrogen receptor-alpha and -beta in regulating leptin expression in 3T3-L1 adipocytes. | We investigated the effects of the estrogen receptor-alpha (ERalpha) and -beta (ERbeta) in the regulation of leptin, resistin, and adiponectin expression in 3T3-L1 adipocytes. Mature adipocytes were exposed to estradiol (E2), ERalpha agonist (PPT (4,4',4''-(4-propyl-[1H]-pyrazole-1,3,5-triyl)trisphenol)), ERbeta agonist (DPN (2,3-bis(4-Hydroxyphenyl)-propionitrile)), E2 with ERalpha antagonist (MPP (1,3-Bis(4-hydroxyphenyl)-4-methyl-5-[4-(2-piperidinylethoxy)phenol]-1H-pyrazole dihydrochloride)), and E2 with ERbeta antagonist (R,R-THC ((R,R)-5,11-diethyl-5,6,11,12-tetrahydro-2,8-chrysenediol)) at different concentrations. To clarify the expression and regulation of adipokines by ER subtypes, total RNA was extracted from cells and measured using quantitative PCR. Western blot analysis was performed to evaluate the protein expression of adipokines, ERalpha, and ERbeta. The leptin expression was significantly increased in the cells treated with high concentrations (10(-5) and 10(-6) mol/l) of the PPT (P < 0.01, P < 0.05). By contrast, the leptin expression decreased in a dose-dependent manner in the MPP-treated groups (P < 0.05). High concentrations (10(-5) mol/l) of R,R-THC with E2 (10(-7) mol/l) caused a significant increase of the leptin expression (P < 0.01). The leptin mRNA levels were positively correlated with the ERalpha mRNA levels (r = 0.584, P < 0.01) and negatively correlated with the ERbeta mRNA levels (r = -0.236, P = 0.03) in the adipocytes. The ratio of the ERalpha to ERbeta mRNA levels in the adipocytes was significantly associated with leptin mRNA levels (r = 0.454, P < 0.01). ERalpha induced leptin expression and ERbeta inhibited its expression in 3T3-L1 adipocytes. The ratio of the ERalpha-to-ERbeta expression in 3T3-L1 adipocytes may be an important potential regulatory factor in leptin expression. | 18,719,660 |
Weight loss maintenance in a population-based sample of German adults. | The objective of this study was to investigate the prevalence of weight loss maintenance in a population-based sample of the German adult population. German adults were recruited based on the random digital-dialing methodology. Using computer-assisted telephone interviewing, weight loss maintenance was assessed, defined as having intentionally lost at least 10% from maximum weight and having maintained it for at least 1 year at the time of the survey. A total of 2,095 noninstitutionalized adults were randomly selected from all parts of Germany and the data of 957 respondents were included into the analysis. Of those who were at least overweight (BMI >or= 25 kg/m(2)) at their maximum weight, 17.7% reported having maintained a current weight loss of >or=10% of their maximum weight for at least 1 year. Among participants who reported a maximum weight in the obese range (BMI >or= 30 kg/m(2)), 29.7% reported successful 1-year weight loss maintenance. Among at least overweight participants, being younger and female, and having a higher maximum BMI were significant predictors of successful 1-year weight loss maintenance. The results suggest that successful weight loss maintenance is not uncommon in the general population, particularly in formerly obese participants. More should be learned about the strategies that successful weight maintainers use to avoid regaining weight. | 18,719,662 |
Retinol-binding protein 4, visceral fat, and the metabolic syndrome: effects of weight loss. | Retinol-binding protein 4 (RBP-4) has been reported to be associated with visceral-fat accumulation and parameters of the metabolic syndrome (MetS). In this study, we investigated the relationship between RBP-4, visceral fat, and the MetS during pronounced weight loss after bariatric surgery. Thirty-six subjects were examined before and 2 years after surgery. Abdominal-fat distribution was determined by ultrasound, metabolic parameters, and serum RBP-4 levels by standard methods. After surgery BMI decreased by 9.07 kg/m(2), visceral-fat diameter (VFD) decreased by 60.6%, and RBP-4 serum levels by 16.6%. Change of RBP-4 levels was associated with reductions of waist (r = 0.364, P = 0.037), waist-to-hip ratio (WHR) (r = 0.415, P = 0.016), and VFD (r = 0.425, P = 0.010). MetS, as defined by International Diabetes Federation (IDF), was present in 19 patients at baseline and in nine patients at follow-up. Change in RBP-4 levels was the best predictor for the diagnosis of MetS at follow-up. In the subgroup without MetS at baseline, the decrease in RBP-4 levels (-28.1% vs. -6.3%, P = 0.020) and reduction in VFD (-66.9% vs. -55.0%, P = 0.038) were significantly greater compared to the subgroup with MetS. We demonstrate a marked decrease of RBP-4 levels after bariatric surgery, which correlates with reduction in visceral-fat mass. Furthermore, the extent of changes in RBP-4 levels differs according to the severity of the MetS. | 18,719,670 |
Calcium supplementation does not alter lipid oxidation or lipolysis in overweight/obese women. | Based on cell culture and studies in mice, increased dietary calcium appears to stimulate lipolysis and could possibly reduce body adiposity through hormonal influences on adipocyte calcium uptake. In this study, we investigated the effects of 1,500 mg supplemental calcium daily for 3 months on hormones regulating calcium and energy metabolism and rates of lipid oxidation and lipolysis in overweight women. Fifteen overweight (BMI > 25 kg/m(2)) premenopausal women were supplemented with 1,500 mg of calcium, as CaCO(3), per day for 3 months while maintaining their usual diets and activity levels. Baseline and endpoint measurements were obtained after the subjects consumed a standardized 25% fat diet for 4 days. Lipid oxidation was measured by indirect calorimetry, lipolysis by infusion of deuterated glycerol, and body fat by dual-energy X-ray absorptiometry. Urinary calcium, circulating levels of hormones involved in energy and lipid metabolism (insulin, leptin, and adiponectin) or calcium metabolism (25(OH)D, 1,25(OH)(2)D), and parathyroid hormone (PTH)) were also measured. Urinary levels of calcium (P = 0.005) increased and 1,25(OH)(2)D declined (P = 0.03). However other parameters, including body weight, body fat, PTH, insulin, leptin, adiponectin, 25(OH)D, as well as rates of lipid oxidation and lipolysis were not altered by calcium supplementation. Calcium supplementation for 3 months increased urinary calcium excretion, decreased circulating levels of 1,25(OH)(2)-D, but had no effect on rates of lipid oxidation or lipolysis, in these overweight women. | 18,719,672 |
Conserved functions of the pRB and E2F families. | Proteins that are related to the retinoblastoma tumour suppressor pRB and the E2F transcription factor are conserved in many species of plants and animals. The mammalian orthologues of pRB and E2F are best known for their roles in cell proliferation, but it has become clear that they affect many biological processes. Here we describe the functions of pRB-related proteins and E2F proteins that have emerged from genetic and biochemical experiments in Caenorhabditis elegans and Drosophila melanogaster. The similarities that have been observed between worms, flies and mammals provide insight into the core activities of pRB and E2F proteins and show how a common regulatory module can control various biological functions in different organisms. | 18,719,710 |
Role of the caudal pressor area in the regulation of sympathetic vasomotor tone. | It is well known that the ventrolateral medulla contains neurons involved in the tonic and reflex control of the cardiovascular system. Two regions within the ventrolateral medulla were initially identified: the rostral ventrolateral medulla (RVLM) and the caudal ventrolateral medulla (CVLM). Activation of the RVLM raises arterial blood pressure and sympathetic nerve activity, and activation of the CVLM causes opposite effects. The RVLM premotor neurons project directly to sympathetic preganglionic neurons and are involved in the maintenance of resting sympathetic vasomotor tone. A significant proportion of tonic activity in the RVLM sympathetic premotor neurons is driven by neurons located in a third region of the ventrolateral medulla denominated caudal pressor area (CPA). The CPA is a pressor region located at the extreme caudal part of the ventrolateral medulla that appears to have an important role controlling the activity of RVLM neurons. In this brief review, we will address the importance of the ventrolateral medulla neurons for the generation of resting sympathetic tone related to arterial blood pressure control focusing on two regions, the RVLM and the CPA. | 18,719,736 |
DNA sequencing confirms the involvement of Leishmania (L.) amazonensis in American tegumentary leishmaniasis in the state of São Paulo, Brazil. | American tegumentary leishmaniasis (ATL) represents one of the most important public health issues in the world. An increased number of autochthonous cases of ATL in the Northeastern region of São Paulo State has been documented in the last few years, leading to a desire to determine the Leishmania species implicated. PCR followed by DNA sequencing was carried out to identify a 120bp fragment from the universal kDNA minicircle of the genus Leishmania in 61 skin or mucosal biopsies from patients with ATL. DNA sequencing permitted the identification of a particular 15bp fragment (5' GTC TTT GGG GCA AGT... 3') in all samples. Analysis by the neighbor-joining method showed the occurrence of two distinct groups related to the genus Viannia (V) and Leishmania (L), each with two subgroups. Autochthonous cases with identity to a special Leishmania sequence not referenced in Genbank predominated in subgroup V.1, suggesting the possible existence of a subtype or mutation of Leishmania Viannia in this region. In the subgroup L.2, which showed identity with a known sequence of L. (L.) amazonensis, there was a balanced distribution of autochthonous and non-autochthonous cases, including the mucosal and mucocutaneous forms in four patients. The last observation may direct us to new concepts, since the mucosal compromising has commonly been attributed to L. (V.) braziliensis, even though L. (L.) amazonensis is more frequent in the Amazonian region. These results confirm the pattern of distribution and possible mutations of these species, as well as the change in the clinical form presentation of ATL in the São Paulo State. | 18,719,754 |
Evaluation of physical activity habits in patients with posttraumatic stress disorder. | In this study, we present data from a survey that aimed to assess the physical activity habits of adult Brazilian patients with Posttraumatic Stress Disorder. Fifty male and female patients with Posttraumatic Stress Disorder participated in this study. The mean age at onset was 37+/-12 years, and the mean time between diagnosis and follow-up was 3.6+/-4.2 years. Substantial changes in physical activity habits were observed following the onset of PTSD. While more than half of the patients participated in physical activities prior to Posttraumatic Stress Disorder onset, there was a significant reduction in their participation afterwards. The justifications for stopping physical activities or sport participation were lack of time and lack of motivation. Several studies have shown that physical exercise decreases reverts symptoms of psychiatric disorders such as depression, anxiety and social isolation. We could therefore hypothesize that patients with Posttraumatic Stress Disorder who exercise should experience the same benefits. Our findings demonstrated that patients with Posttraumatic Stress Disorder have low levels of participation in sports or physical activities. | 18,719,757 |
International meeting: new diagnostic tests are urgently needed to treat patients with Chagas disease. | Trypanosoma cruzi infection is often not detected early on or actively diagnosed, partly because most infected individuals are either asymptomatic or oligosymptomatic. Moreover, in most places, neither blood banks nor healthcare units offer diagnostic confirmation or treatment access. By the time patients present clinical manifestations of advanced chronic Chagas disease, specific treatment with current drugs usually has limited effectiveness. Better-quality serological assays are urgently needed, especially rapid diagnostic tests for diagnosis patients in both acute and chronic phases, as well as for confirming that a parasitological cure has been achieved. Some new antigen combinations look promising and it is important to assess which ones are potentially the best, together with their requirements in terms of investigation and development. In August 2007, a group of specialized researchers and healthcare professionals met to discuss the state of Chagas infection diagnosis and to build a consensus for a plan of action to develop efficient, affordable, accessible and easy-to-use diagnostic tests for Chagas disease. This technical report presents the conclusions from that meeting. | 18,719,818 |
[Aortic arch surgery with bilateral cerebral perfusion by isolation of brachiocephalic trunk and left carotid artery]. | To evaluate the results of a technique described by Carreira et al. using bilateral antegrade selective cerebral perfusion by isolating the brachiocephalic trunk and the left carotid artery. Fifteen patients were operated between June 2005 and September 2007. Data analysis were performed using Epi Info and statistical significance was set at p<0.05. Of the 15 patients, 53.3% were male; mean age was 59.86+/-15.4 years; 60% presented with type A acute aortic dissection; 6.7% type B; and 33.3% aneurysm of aorta and arch. Mean CPB and aortic clamping time was 177.6+/-39.4 and 135.9+/-34.0 minutes, respectively. In this group, 86.7% were not submitted to total circulatory arrest, with mean unilateral and bilateral selective cerebral perfusion time of 10.9+/-2.0 and 57.2+/-21.2 minutes, respectively. Mean hypothermic temperature was 23.0+/-2.9 masculineC. Two had left subclavian artery ligature, 60% used separated aortic grafts, and four used aortic endoprosthesis. Three (20%) patients died, all of them in the acute aortic dissection group. There were no neurological complications. The mean follow up time was 11.7+/-9.6 months. Regarding mortality, none of the parameters were statistically significant (p>0.05). The technique of bilateral selective cerebral perfusion described by Carreira et al. can be performed by others and presents similar results to the international literature. The excellent neurological outcome and easy bleeding control on surgical sutures lines are the major advantages of this new procedure. | 18,719,831 |
[Coronary aneurysm after drug-eluting stent implantation]. | The use of drug-eluting stents aiming at by-pass the disadvantage of stainless steel stents have been associated to late thrombosis after withdrawal of anti-platelet agents. We report a case with another complication, the development of a coronary aneurysm in the stent area more than three years after index procedure. Late chronic local inflammatory responses may be responsible for the weakening, erosion and aneusrysm formation. | 18,719,840 |
Beliefs about mental health problems and help-seeking behavior in Dutch young adults. | Mental health problems in young adults are frequent and impairing, but are often left untreated. This study among young adults with self-perceived mental health problems examines beliefs about mental health problems (i.e. their cause, consequences, timeline, and controllability) and help-seeking behaviour. A cross-sectional population survey (n = 2,258) in the south-west Netherlands. Participants were included who reported having mental health problems during the past year (n = 830). Beliefs about cause, consequences, timeline, and controllability of self-perceived mental health problems were assessed with the Illness Perception Questionnaire. Internalizing and externalizing psychopathology was assessed with the Adult Self-Report. A multivariate logistic regression analysis indicates that independent of sex, age, and severity of psychopathology, higher levels on the intra-psychic causes scale (OR = 1.95, 95%CI = 1.48-2.58), the consequences scale (OR = 1.81, 95%CI = 1.40-2.33), and the treatment control scale (OR = 1.97, 95%CI = 1.60-2.41) are associated with an increased likelihood of mental health service use, while higher levels of personal control (OR = 0.76, 95%CI = 0.62-0.93) are associated with a decreased likelihood. Beliefs that may encourage young adults with mental health problems to seek professional help include the beliefs that mental health problems have adverse consequences and that treatment can help. Since these beliefs are related to young adults' knowledge of mental health problems, help-seeking behavior may be encouraged by educating young adults about mental health problems and the effective mental health treatments which are available. | 18,719,849 |
Outcomes of surgical treatment of diabetic foot osteomyelitis: a series of 185 patients with histopathological confirmation of bone involvement. | We analysed the factors that determine the outcomes of surgical treatment of osteomyelitis of the foot in diabetic patients given early surgical treatment within 12 h of admission and treated with prioritisation of foot-sparing surgery and avoidance of amputation. A consecutive series of 185 diabetic patients with foot osteomyelitis and histopathological confirmation of bone involvement were followed until healing, amputation or death. Probing to bone was positive in 175 cases (94.5%) and radiological signs of osteomyelitis were found in 157 cases (84.8%). Staphylococcus aureus was the organism isolated in the majority of cultures (51.3%), and in 35 cases (36.8%) it proved to be methicillin-resistant. The surgical treatment performed included 91 conservative surgical procedures, which were defined as those where no amputation of any part of the foot was undertaken (49.1%). A total of 94 patients received some degree of amputation, consisting of 79 foot-level (minor) amputations (42.4%) and 15 major amputations (8%). Five patients died during the perioperative period (2.7%). Histopathological analysis revealed 94 cases (50.8%) of acute osteomyelitis, 43 cases (23.2%) of chronic osteomyelitis, 45 cases (24.3%) of acute exacerbation of chronic osteomyelitis and three remaining cases (1.6%) designated as 'other'. The risks of failure in the case of conservative surgery were exposed bone, the presence of ischaemia and necrotising soft tissue infection. Conservative surgery without local or high-level amputation is successful in almost half of the cases of diabetic foot osteomyelitis. Prospective trials should be undertaken to determine the relative roles of conservative surgery versus other approaches. | 18,719,880 |
[On the biomechanics of the hip: relevance of femoral anteversion for hip contact force and loading using a short-stemmed prostheses]. | Short-stemmed hip implants were established in total hip arthroplasty in the last years. Also patients with secondary osteoarthritis of the hip with pathological anteversion of the femoral neck are treated increasingly using this method. Therefore an investigation was performed to analyze the resulting hip contact force and femoral loading in the proximal femur at the solid model of the "standardized femur". Two different situations of femoral component anteversion were simulated. Increased hip contact forces and an increase of medial and lateral cortex loads result in the anteverted model. With present level of knowledge about the influence of the hip contact force the use of short-stemmed implants is not uncritically in patients with degenerative osteoarthritis of the hip combined with rotational disorders of the proximal femur. The selection of the tribological pairing is to be considered more strongly regarding the wear behavior. | 18,719,885 |
Factors predicting the failure of Bernese periacetabular osteotomy: a meta-regression analysis. | There is no clear evidence regarding the outcome of Bernese periacetabular osteotomy (PAO) in different patient populations. We performed systematic meta-regression analysis of 23 eligible studies. There were 1,113 patients of which 61 patients had total hip arthroplasty (THA) (endpoint) as a result of failed Bernese PAO. Univariate analysis revealed significant correlation between THA and presence of grade 2/grade 3 arthritis, Merle de'Aubigne score (MDS), Harris hip score and Tonnis angle, change in lateral centre edge (LCE) angle, late proximal femoral osteotomies, and heterotrophic ossification (HO) resection. Multivariate analysis showed that the odds of having THA increases with grade 2/grade 3 osteoarthritis (3.36 times), joint penetration (3.12 times), low preoperative MDS (1.59 times), late PFO (1.59 times), presence of preoperative subluxation (1.22 times), previous hip operations (1.14 times), and concomitant PFO (1.09 times). In the absence of randomised controlled studies, the findings of this analysis can help the surgeon to make treatment decisions. | 18,719,916 |
Higher LPS-stimulated TNF-alpha mRNA levels in peripheral blood mononuclear cells from Chinese ankylosing spondylitis patients with -308G/A polymorphism in promoter region of tumor necrosis factor: association with distinct A33/B58/Cw10 haplotypes. | To investigate the effects of TNF-alpha -308, -238 promoter polymorphisms on TNF-alpha transcription in B27 positive Chinese patients with ankylosing spondylitis (AS). The possible relationship between polymorphisms, MHC antigens, and quantitative TNF-alpha mRNA expression were evaluated. Single nucleotide polymorphisms (SNPS) of TNF-alpha -308 and -238 were performed by PCR-amplification refractory mutation system method (PCR-ARMS) in sixty-seven B27-positive AS patients and 60 HLA-B27 positive healthy controls in Chinese. Quantitative measurement of TNF-alpha mRNA in peripheral blood mononuclear cells was performed with real time RT-PCR. The polymorphisms were correlated to quantitative TNF-alpha mRNA, and MHC antigens (determined by SSP method) in AS patients. The prevalence rate of both -308G/A and -238G/A TNF-alpha promoter polymorphisms in patients were not significantly different from those in normal subjects. However, a significant high LPS-stimulated TNF-alpha mRNA expression was found in peripheral blood mononuclear cells from patients with promoter -308G/A polymorphism (TNF2) as compared to those in -308G/G genotype (TNF1). Furthermore, -308G/A polymorphism in patients was found to be tightly associated with distinct haplotypes of A33/B58/Cw10 [12 out of 14 -308G/A patients (85.7%) versus none in 53 -308G/G patients], independent of B27 antigen. HLA-A33-B58-Cw10 haplotypes associated TNF-alpha promoter -308G/A polymorphism might play an important role in disease pathogenesis of AS in Chinese population, partially related to a driving force of a higher TNF-alpha production. It confirms once again the importance and complexity of MHC related molecules in disease pathogenesis of AS. | 18,719,920 |
Sublaminar wiring stabilization to prevent adjacent segment degeneration after lumbar spinal fusion. | Adjacent segment degeneration (ASD) is a complication of lumbar spinal fusion. There are some reports on the cause of this degeneration but none concerning its prevention. We performed sublaminar wiring stabilization to prevent ASD after posterolateral lumbar spinal fusion with instrumentation. The purpose of this study was to prospectively evaluate the efficacy of this procedure. Between 2003 and 2004, 54 consecutive patients with lumbar spinal canal stenosis and multilevel instability of the lumbar spine underwent posterior decompression and posterolateral fusion with instrumentation. The mean age at the time of surgery was 66.7 +/- 1.3 years, and the mean follow-up period was 40.0 +/- 1.1 months, with a minimum of 29 months. Twenty-seven of the patients underwent conventional sublaminar wiring stabilization at the cephalad segment adjacent to the site of fusion to prevent ASD (group A), and the other 27 patients did not (group B). Some items were assessed, including clinical outcome using Japanese Orthopaedic Association (JOA) score, sagittal global lumbar alignment, and segmental motion in flexion-extension radiographs of the cephalad vertebral body adjacent to the site of fusion. There were no significant differences in JOA scores between two groups, but 2 patients in group B underwent subsequent surgery due to ASD. Sagittal lumbar alignment did not change in group A but was significantly decreased in group B. With respect to segmental motion in flexion-extension radiographs, group A showed a significant decrease from 6.9 degrees before surgery to 3.4 degrees after surgery, on the other hand group B showed a significant increase from 5.6 degrees before surgery to 8.4 degrees after surgery. In this study, it was suggested that sublaminar wiring stabilization significantly reduces the range of motion of the adjacent segment and preserves sagittal lumbar alignment, which lead to prevention of ASD. The clinical outcome of the subsequent surgeries is relatively poor, so it is important to prevent ASD by any prevention such as sublaminar wiring stabilization. | 18,719,930 |
Arseniasis prevalence and mortality in a multiethnic, endemic township in Guizhou, China. | Farmers in Southwest Guizhou Autonomous Prefecture, China, represent a unique case of arseniasis, which is related to indoor combustion of high arsenic-containing coal instead of to arsenic-contaminated drinking water. A significant difference in the prevalence of arseniasis was observed in two neighboring ethnic clans in one village. The question arose whether the ethnicity-dependent difference observed in this village was more widely spread throughout the whole township. An epidemiologic investigation was designed to explore arseniasis distribution and mortality among all four ethnic groups in a multiethnic township. The cohort of arseniasis patients, diagnosed and registered in the overall field survey of 1991 as well as all the asymptomatic residents of the township, were enrolled in the present investigation. Indirect standardization was used for calculating the age-adjusted standardized incidence ratio (SIR) of arseniasis, the standardized mortality ratio (SMR) of various death causes (including some cancers), and their corresponding intervals of 95% confidence in both genders and in each local ethnic group. The descending rank of arseniasis SIRs among local ethnic groups was found as: Hui>Han>Bouyei>Hmong. The descending rank of SMRs of malignancies was displayed as: Han>Hui>Bouyei>Hmong in males and both genders together as well. Concerning deaths of non-malignant causes the rank was observed as: Hui>Han>Bouyei>Hmong in males. The arseniasis SIR for ethnic Hmong residents (both genders combined) was found to be significantly less profound than the overall level in the township. No death cases in diagnosed ethnic Hmong patients and no cases of death from malignant causes in asymptomatic Hmong residents were recorded. The significant increase of arseniasis prevalence was observed in all males, compared with the overall prevalence of all residents. However, a significantly lower prevalence was seen in all females. Significant ethnicity-dependent difference in arseniasis prevalence and mortality from all causes was found in a multiethnic rural township where farmers have been exposed to the indoor combustion of high arsenic coal for decades. The ethnic Hmong residents seemed to be the least susceptible to arseniasis among the four local ethnic groups. | 18,719,935 |
Visually guided capture of a moving stimulus by the pigeon (Columba livia). | Although the pigeon is a popular model for studying visual perception, relatively little is known about its perception of motion. Three experiments examined the pigeons' ability to capture a moving stimulus. In Experiment 1, the effect of manipulating stimulus speed and the length of the stimulus was examined using a simple rightward linear motion. This revealed a clear effect of length on capture and speed on errors. Errors were mostly anticipatory and there appeared to be two processes contributing to response locations: anticipatory peck bias and lag time. Using the same birds as Experiment 1, Experiment 2 assessed transfer of tracking and capture to novel linear motions. The birds were able to capture other motion directions, but they displayed a strong rightward peck bias, indicating that they had learned to peck to the right of the stimulus in Experiment 1. Experiment 3 used the same task as Experiment 2 but with naïve birds. These birds did not show the rightward bias in pecking and instead pecked more evenly around the stimulus. The combined results indicate that the pigeon can engage in anticipatory tracking and capture of a moving stimulus, and that motion properties and training experience influence capture. | 18,719,954 |
A chip for catching, separating, and transporting bio-particles with dielectrophoresis. | This study aims at developing a 3D device for catching, separating, and transporting bio-particles based on dielectrophoresis (DEP). Target particles can be simultaneously caught and transported using the negative DEP method. In non-uniform electric fields, the levitation height or complex permittivity of certain particle may be different from that of another and this property can facilitate separation of particles. We have designed and constructed a 3D device consisting of two layers of electrodes separated by a channel formed by 50 microm thick photoresist. The electrodes can operate effectively with 10-15 V and 5-7 MHz to catch all particles in the channel, and can move particles after switching the electric field to 5-15 V and 500-1,000 KHz. Hence, particles experienced coupling force of two different directional twDEP forces, and tallied with our estimation to move along the coupling direction. | 18,719,958 |
Living with long QT syndrome: a qualitative study of coping with increased risk of sudden cardiac death. | Long QT syndrome (LQTS) is a congenital disorder associated with increased risk of sudden cardiac death; LQTS patients and their families are offered diagnostic or predictive genetic testing. The purpose of this qualitative study was to investigate the psychosocial aspects of living with LQTS, to identify LQTS patients' daily life challenges and coping strategies, and to describe their experiences with healthcare services. In-depth interviews were conducted with seven individuals who had been tested for long QT genetic mutation. Four of these participants had an implantable cardiac defibrillator (ICD). The participants reported that early and gradually acquired knowledge of the syndrome was an advantage. They also reported experiencing worries and limitations in daily life, but their main concern was for their children or grandchildren. Healthcare providers' minimal knowledge of LQTS resulted in uncertainty, misinformation, and even wrong advice regarding treatment. The results suggest that regional centers, with the appropriate expertise, should investigate and counsel LQTS patients and their families. | 18,719,982 |
Moderators of sexual behavior in gay men. | We investigated factors that might moderate the association between sexual behavior desires and sexual behavior enactments in gay men. Condom eschewal, number of STIs, HIV serostatus, age, and relationship status were each hypothesized to moderate this association. An Internet survey collected data from 219 self-identifying gay men. Results indicated that sexual behavior desires and enactments were highly correlated, and of the five moderators tested, four varied this association. Condom eschewers had a stronger association between desires and enactments than condom users. Gay men with fewer STIs/STDs (excluding HIV) also had a stronger association between the two variables. HIV serostatus did not exclusively moderate the association. Rather, a three-way interaction was produced such that HIV-positive men with STIs had a stronger association between sexual behavior desires and enactments than HIV-negative men with STIs. Finally, gay men in monogamous relationships were least likely to have their desires associated with enactments. Age was not found to be a significant moderator. Overall, we concluded the moderators representing sexual health and sexual health behaviors were most influential over the enactment of sexual behavior desires. | 18,719,988 |
Maternal and genetic effects on the acoustic startle reflex and its sensitization in C3H/HeN, DBA/2JHd and NMRI mice following blastocyst transfer. | In the present study, reciprocal embryo transfers were conducted to examine genetic and maternal effects on the baseline and fear-sensitized acoustic startle response (ASR) in the two inbred strains C3H/HeN and DBA/2JHd and the outbred strain NMRI. The largest differences in the ASR were found in untreated strains (effect size 0.6). The transfer procedure per se had a significant effect on the behavior of NMRI mice resulting in a reduction in the baseline, and an increase in the fear-sensitized ASR. In contrast, there were no significant effects of the transfer procedure in the two inbred strains. Autosomal genetic effects had a stronger impact on the amplitude of the ASR (effect sizes 0.5) than sex (effect sizes 0.06) as revealed by reciprocal embryo transfer. Nevertheless, the genetic effects on the fear-sensitized ASR were somewhat more variable and strain-dependent (effect sizes 0.1-0.2). Global maternal effects were detected after embryo transfer into NMRI mothers resulting in a larger reduction of the ASR in the offspring of DBA and NMRI donors than C3H donors (effect sizes 0.1-0.2). An additional fostering procedure was introduced to dissect uterine and postnatal maternal effects in NMRI offspring. Uterine factors changed the baseline ASR of the offspring in direction of the recipient mother strain. Surprisingly, postnatal maternal effects on the ASR were contrary to the behavior of the rearing mother. In conclusion, both genetic and prenatal/postnatal maternal factors persistently influenced the ASR of the offspring, whereas the fear-sensitized ASR was mainly influenced by genetic factors. Our study shows that uterine and postnatal maternal influences deserve more attention when determining the phenotype of genetically engineered mice at least in the first generation following embryo transfer. | 18,719,991 |
Lysosulfatide regulates the motility of a neural precursor cell line via calcium-mediated process collapse. | Lysosulfatide is a derivative of the glycosphingolipid sulfatide. It is a major component of high density lipoproteins and was detected in the human brain. Here, we show that lysosulfatide acts as an extracellular signal regulating the migration of a neural precursor cell line (B35 neuroblastoma cells) by rapidly promoting process retraction and cell rounding. These cells express the lysosulfatide receptor S1P3 according to RT-PCR, western blotting and immunocytochemistry, but S1P3 does not mediate the effect since preincubation with three different compounds known to inhibit S1P3 did not block lysosulfatide-induced cell rounding. The signal transduction after stimulation with 3 microM lysosulfatide involves a rapid increase of [Ca2+]i which causes process retraction. This mechanism may be relevant under conditions where neural cells encounter elevated lysosulfatide levels as for example under pathological conditions after breakdown of the blood brain barrier or possibly in the lysosomal sulfatide storage disorder metachromatic leukodystrophy. | 18,719,997 |
The effects of melatonin on colonic transit time in normal controls and IBS patients. | The role of melatonin in regulating gut motility in human subjects is not clear. The aim of this study was to investigate the effects of exogenous melatonin on colonic transit time (CTT) in healthy subjects and in patients with irritable bowel syndrome (IBS). Colonic transit time was measured in 17 healthy controls using the radio-opaque, blue dye, and Bristol stool form score method before and after 30 days of melatonin treatment 3 mg daily. A double blind cross-over study aimed at measuring CTT was also performed in 17 matched IBS patients using the blue dye and Bristol stool form score methods. The patients were randomized and received either melatonin 3 mg or placebo daily for 8 weeks, followed by a 4-week washout, and then placebo or melatonin in the reverse order for a second 8-week period. The melatonin treatment of the control subjects caused an increase in CTT (mean+/-SD) from 27.4+/-10.5 to 37.4+/-23.8 h (P=0.04). Compared with the CTT of the controls (25.2+/-7.7), that of the constipation-predominant IBS patients appeared prolonged-65.2+/-33.3 h (P<0.01). The CTT did not change significantly in IBS patients after melatonin treatment. Melatonin may be a promising candidate for the future research of agents that can modulate bowel motility. | 18,720,001 |
Irritable bowel syndrome and gastroesophageal reflux disease in primary care: is there a link? | Population-based studies have shown that gastroesophageal reflux disease (GERD) and irritable bowel syndrome (IBS) coexist more commonly than expected by chance. We aimed to investigate the relationship between GERD and IBS in primary care. The General Practice Research Database was used to identify patients with a first diagnosis of GERD (n=6,421) or IBS (n=2,932). Patients were followed up for 12 months after diagnosis to investigate the incidence of IBS among GERD patients and GERD among IBS patients. The relative risk (RR) of developing IBS was 3.5 (95% CI: 2.3-5.4) in the GERD cohort compared with the comparison cohort. The RR of developing GERD was 2.8 (95% CI: 1.7-4.9) in the IBS cohort compared with the comparison cohort. A first diagnosis of either IBS or GERD significantly increases the risk of a subsequent diagnosis of the other condition. | 18,720,002 |
Conjugated linoleic acid-induced toxic hepatitis: first case report. | A 46-year-old female patient was referred to our department with presenting symptoms of asthenia, jaundice, and pruritus. There was no medical history or clinical evidence of viral hepatitis, autoimmune hepatitis, hemochromatosis, or Wilson's disease. The patient revealed that 14 days prior to admission she had begun self-medicating with conjugated linoleic acid (CLA) to reduce body fat, leading to the suspicion of CLA hepatotoxicity, which was subsequently confirmed by a liver biopsy. After the patient ceased to ingest CLA, liver enzymes levels normalized. To the best of our knowledge, this is the first report of hepatotoxicity due to CLA ingestion. | 18,720,003 |
Non-traditional metabolic pathways of adrenal steroids. | Metabolic pathways are reconstructed from biochemical evidence to conceptualize the predominant route to important biomolecules. Pathways have heuristic value in their capacity to explain the metabolic derangements in genetic diseases of enzyme deficiencies and during pharmacologic inhibition of these enzymes. Implicit in the description of these pathways is the potential existence of alternate routes, variable order of reactions, and the inevitable by-products generated by incomplete efficiencies and competing enzymes. This chapter will consider alternate fates encountered by steroid hormone precursors in the adrenal gland, the variables influencing flux through these secondary pathways, and the significance of these diversions in health and disease. | 18,720,009 |
Neuron and gliocyte death induced by photodynamic treatment: signal processes and neuron-glial interactions. | The mechanisms of photodynamic (PD) damage to neurons and gliocytes are discussed. The spike reactions of neurons are described, with stimulation at high concentrations of photosensitizer and inhibition at low concentrations, accompanying necrosis. Glial cells developed both necrosis and apoptosis. Local laser inactivation of neurons increased light-induced apoptosis of gliocytes, i.e., neurons maintained gliocyte survival. Inter-and intracellular signaling plays an important role in the photolesioning of these cells. Studies using inhibitors and activators of signal proteins demonstrated the involvement of the Ca(2+)-dependent, adenylate cyclase, and tyrosine kinase pathways in the responses of neurons and gliocytes to PD treatment. Pharmacological modulation may alter the selectivity of PD neuron and gliocyte damage and the efficacy of PD treatment. | 18,720,010 |
Does single embryo transfer improve the obstetric and neonatal outcome of singleton pregnancy? | Singleton pregnancies following in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI) are associated with increased risks of abnormal placentation, pre-eclampsia and preterm birth. These risks might partly be a consequence of the number of transferred embryos. In this commentary we summarize the results of three observational studies and one randomized study with 1052 pregnancies following single embryo transfer (SET). An increased age- and parity-adjusted risk of gestational hypertension and placenta previa in the SET pregnancies as compared to the spontaneously conceiving controls was reported in one of the studies. Preterm births occurred in 6-12% of SET pregnancies and 4-6% of the newborns were of low birth weight (LBW). The frequency of preterm birth and LBW after SET were considered either lower than or similar to those after double embryo transfer (DET) but higher than after spontaneous conception. Comparison of SET and DET pregnancies thus shows heterogeneous results. Still, it seems that not even a transfer of one good-quality embryo at a time diminishes all the previously identified increased risks of certain obstetric complications and preterm births in singleton pregnancies following IVF or ICSI. | 18,720,030 |
IVF pregnancies: neonatal outcomes after the new Italian law on assisted reproduction technology (law 40/2004). | To compare maternal and neonatal outcome of pregnancies achieved by assisted reproduction technique (ART) according to the guidelines of the newly established Italian ART law 40/2004, with that of naturally conceived. Three hundred and sixty-four ART pregnancies and 304 naturally conceived pregnancies were analyzed in terms of the incidence of obstetric complications and perinatal outcome. Control group was enrolled prospectively after being matched for an extensive number of maternal characteristics. Among singletons, ART pregnancies when compared to naturally conceived pregnancies showed a higher incidence of pregnancy loss (23.4% versus 10.5%) and a lower mean birth weight. A higher but not significant incidence of small for gestational age fetuses was observed in ART pregnancies, compared to those from normally conceived pregnancies (7.2% versus 2.7%). Moreover, the ART pregnancies showed a slightly, but nonetheless significantly shorter mean gestational age (38.6 versus 39.3 weeks) and more frequent preterm deliveries (11%) than the control group (2.7%). No difference was found in terms of other obstetric complications such as pregnancy-induced hypertension, gestational diabetes and placental abruption. Neonatal outcome was similar in both groups. Although the obstetric outcome among singleton ART pregnancies was good, these patients should be considered obstetric risk cases. The different frequency of complications is not related to maternal age or parity and could be the consequence of infertility or the procedures by which these women conceived. The reasons are, however, unclear and further studies are necessary. | 18,720,037 |
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