title stringlengths 0 1.13k | abstract stringlengths 1 15.7k | PMID int64 22 36.5M |
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S1P receptor signalling and RGS proteins; expression and function in vascular smooth muscle cells and transfected CHO cells. | Sphingosine-1-phosphate (S1P) signalling via G protein-coupled receptors is important for the regulation of cell function and differentiation. Specific Regulators of G protein Signalling (RGS) proteins modulate the function of these receptors in many cell types including vascular smooth muscle cells (VSMCs). Therefore, we investigated the role of altered expression levels of RGS proteins in S1P receptor function in VSMCs and transfected CHO cells. The mRNA expression of the S1P(1) receptor, RGS4 and RGS16 were down-regulated in VSMCs during phenotypic modulation induced by culturing, whereas mRNA levels of RGS2, RGS3, S1P(2) and S1P(3) receptors were unchanged. Interestingly, the expression level of RGS5 was transiently up-regulated. Despite major alterations in RGS levels, S1P-induced calcium elevation in VSMCs was not altered. Co-transfection of RGS2, RGS3, RGS4, RGS5 and RGS16 into CHO-Flp-In cells stably expressing the S1P(1) or S1P(3) receptor did not modify S1P-induced inhibition of cAMP accumulation to a major extent. Similar results were obtained with SEW2871, a selective S1P(1) receptor agonist. However, the inhibition of cAMP accumulation by the agonist FTY720-P via the S1P(1) receptor was significantly decreased by co-transfection with RGS5. These results indicate that mRNA of the S1P(1) receptor, RGS4, RGS5 and RGS16 is differentially regulated during phenotypic modulation. However, major alterations in RGS protein expression have only limited effect on S1P receptor function. | 18,854,184 |
Post-natal exposure to corticosterone affects standard metabolic rate in the zebra finch (Taeniopygia guttata). | Post-natal stress has been shown to have important short and long term effects on many adult traits in birds. During stress, metabolic alterations often result in the mobilization of energy away from energy-sensitive functions such as growth, which could have significant implications for developing animals. However, little is known about the implications of stress hormones for energy consumption in growing individuals. We experimentally increased corticosterone (CORT) levels in nestling zebra finches via oral administration, between the ages of 7 and 18 days. The standard metabolic rate (SMR) of birds was measured twice overnight when birds were between 11-13 and 55-65 days of age. Developmental CORT administration significantly elevated overnight variability in SMR (sd) in nestling birds (during the treatment period), but not at 55-65 days (5-6 weeks after the treatment period). The effect on variability was seen more prominently in birds from larger brood sizes and in females. We found no effects of our treatments on mean SMR overnight. However, brood size and sex had interactive effects, with males from larger brood sizes having higher SMR at 55-65 days of age. These results suggest that stress hormones can have significant effects on energy metabolism and possibly nocturnal arousal and sleep fragmentation. However, there were no detectable long term effects of our treatments on SMR, suggesting that these effects are only short-lived, in order to maintain homeostasis in the short term. | 18,854,187 |
Behavioral recovery from acute hypoxia is reliant on leptin. | Individuals affected by hypoxia experience a variety of immune-associated sickness symptoms including malaise, fatigue, lethargy and loss of interest in the physical and social environment. Recently, we demonstrated that the interleukin (IL)-1beta arm of the neuroimmune system was critical to the sickness symptoms caused by hypoxia, and that IL-1 receptor antagonist (IL-1RA), IL-1beta's endogenous inhibitor, was critical to promoting sickness recovery. Here, we report that leptin is key to recovery from hypoxia because it dramatically augmented IL-1RA production in mice. We found that hypoxia increased leptin in white adipose tissue (WAT) which in turn, caused a marked rise in serum IL-1RA. Interestingly, in-vitro, leptin was a more potent inducer of IL-RA, in macrophages, than hypoxia. In leptin receptor defective (db/db) and leptin deficient (ob/ob) mice, sickness recovery from hypoxia was delayed 3-fold. Importantly, in ob/ob mice, leptin administration completely reversed this delayed recovery and induced a marked increase in serum IL-1RA. Finally, leptin administration to normal mice reduced hypoxia recovery time by 1/3 and dramatically increased WAT and serum IL-1RA. Leptin did not alter recovery from hypoxia in IL-1RA knock out mice. These results show that by enhancing IL-1RA production leptin promoted sickness recovery from hypoxia. | 18,854,211 |
Calcium-dependent activation of mitochondrial metabolism in mammalian cells. | Endogenous fluorophores provide a simple, but elegant means to investigate the relationship between agonist-evoked Ca2+ signals and the activation of mitochondrial metabolism. In this article, we discuss the methods and strategies to measure cellular pyridine nucleotide and flavoprotein fluorescence alone or in combination with Ca2+-sensitive indicators. These methods were developed using primary cultured hepatocytes and neurons, which contain relatively high levels of endogenous fluorophores and robust metabolic responses. Nevertheless, these methods are amendable to a wide variety of primary cell types and cell lines that maintain active mitochondrial metabolism. | 18,854,213 |
Silver nanoparticles as a new generation of antimicrobials. | Silver has been in use since time immemorial in the form of metallic silver, silver nitrate, silver sulfadiazine for the treatment of burns, wounds and several bacterial infections. But due to the emergence of several antibiotics the use of these silver compounds has been declined remarkably. Nanotechnology is gaining tremendous impetus in the present century due to its capability of modulating metals into their nanosize, which drastically changes the chemical, physical and optical properties of metals. Metallic silver in the form of silver nanoparticles has made a remarkable comeback as a potential antimicrobial agent. The use of silver nanoparticles is also important, as several pathogenic bacteria have developed resistance against various antibiotics. Hence, silver nanoparticles have emerged up with diverse medical applications ranging from silver based dressings, silver coated medicinal devices, such as nanogels, nanolotions, etc. | 18,854,209 |
Identification and expression of a factor of the DM family in the oyster Crassostrea gigas. | The Pacific oyster Crassostrea gigas is a successive not systematic protandric hermaphrodite. Searching for an ortholog to Dmrt1, a conserved sex determinism factor, we have identified the first complete cDNA of a DM factor in Lophotrochozoa which we have called Cg-DMl (Crassostrea gigas DMRT-like). It is 359aa long, with the DM domain common to all the family factors, and one DMA domain specific to members such as Dmrt4 and Dmrt5. Its gene presents one intron of 598 bp. Real time PCR and in situ hybridization have shown that Cg-DMl was expressed in both sexes, with a significantly higher expression in male than in female gonads at the end of the adult gametogenetic cycle and that a significant peak of expression was observed in spat between 1 and 2 months of age. These results suggest that Cg-DMl may be involved in the development of the gonad and may constitute preliminary clues for future work in order to better understand DM protein evolution. | 18,854,223 |
Taming data. | A challenge in systems-level investigations of the immune response is the principled integration of disparate data sets for constructing predictive models. InnateDB (Lynn et al., 2008; http://www.innatedb.ca), a publicly available, manually curated database of experimentally verified molecular interactions and pathways involved in innate immunity, is a powerful new resource that facilitates such integrative systems-level analyses. | 18,854,235 |
An inhibitor of gram-negative bacterial virulence protein secretion. | Bacterial virulence mechanisms are attractive targets for antibiotic development because they are required for the pathogenesis of numerous global infectious disease agents. The bacterial secretion systems used to assemble the surface structures that promote adherence and deliver protein virulence effectors to host cells could comprise one such therapeutic target. In this study, we developed and performed a high-throughput screen of small molecule libraries and identified one compound, a 2-imino-5-arylidene thiazolidinone that blocked secretion and virulence functions of a wide array of animal and plant Gram-negative bacterial pathogens. This compound inhibited type III secretion-dependent functions, with the exception of flagellar motility, and type II secretion-dependent functions, suggesting that its target could be an outer membrane component conserved between these two secretion systems. This work provides a proof of concept that compounds with a broad spectrum of activity against Gram-negative bacterial secretion systems could be developed to prevent and treat bacterial diseases. | 18,854,237 |
Face recognition using spatially constrained earth mover's distance. | Face recognition is a challenging problem, especially when the face images are not strictly aligned (e.g., images can be captured from different viewpoints or the faces may not be accurately cropped by a human or automatic algorithm). In this correspondence, we investigate face recognition under the scenarios with potential spatial misalignments. First, we formulate an asymmetric similarity measure based on Spatially constrained Earth Mover's Distance (SEMD), for which the source image is partitioned into nonoverlapping local patches while the destination image is represented as a set of overlapping local patches at different positions. Assuming that faces are already roughly aligned according to the positions of their eyes, one patch in the source image can be matched only to one of its neighboring patches in the destination image under the spatial constraint of reasonably small misalignments. Because the similarity measure as defined by SEMD is asymmetric, we propose two schemes to combine the two similarity measures computed in both directions. Moreover, we adopt a distance-as-feature approach by treating the distances to the reference images as features in a Kernel Discriminant Analysis (KDA) framework. Experiments on three benchmark face databases, namely the CMU PIE, FERET, and FRGC databases, demonstrate the effectiveness of the proposed SEMD. | 18,854,252 |
Visual attention on the sphere. | Human visual system makes an extensive use of visual attention in order to select the most relevant information and speed-up the vision process. Inspired by visual attention, several computer models have been developed and many computer vision applications rely today on such models. However, the actual algorithms are not suitable to omnidirectional images, which contain a significant amount of geometrical distortion. In this paper, we present a novel computational approach that performs in spherical geometry and thus is suitable for omnidirectional images. Following one of the actual models of visual attention, the spherical saliency map is obtained by fusing together intensity, chromatic, and orientation spherical cue conspicuity maps that are themselves obtained through multiscale analysis on the sphere. Finally, the consecutive maxima in the spherical saliency map represent the spots of attention on the sphere. In the experimental part, the proposed method is then compared to the standard one using a synthetic image. Also, we provide examples of spots detection in real omnidirectional scenes which show its advantages. Finally, an experiment illustrates the homogeneity of the detected visual attention in omnidirectional images. | 18,854,253 |
Lossless compression of color sequences using optimal linear prediction theory. | In this paper, we present a novel technique that uses the optimal linear prediction theory to exploit all the existing redundancies in a color video sequence for lossless compression purposes. The main idea is to introduce the spatial, the spectral, and the temporal correlations in the autocorrelation matrix estimate. In this way, we calculate the cross correlations between adjacent frames and adjacent color components to improve the prediction, i.e., reduce the prediction error energy. The residual image is then coded using a context-based Golomb-Rice coder, where the error modeling is provided by a quantized version of the local prediction error variance. Experimental results show that the proposed algorithm achieves good compression ratios and it is roboust against the scene change problem. | 18,854,256 |
Immunodiagnostic capabilities of anti-free immunoglobulin light chain monoclonal antibodies. | Overproduction of plasma cell-derived monoclonal free kappa or lambda immunoglobulin light chains (FLCs) is a hallmark of multiple myeloma, AL amyloidosis, and light chain deposition disease. Because these components serve as unique cellular and serologic biomarkers, their detection and quantitation has diagnostic, therapeutic, and prognostic import. In this regard, we have developed monoclonal antibodies (mAbs) that specifically recognize the kappa or lambda FLC products of all known human variable and constant region light chain genes. We now report the results of our studies that have demonstrated the capability of these reagents to measure, in a modified fluid-phase capture enzyme-linked immunosorbent assay (ELISA), serum kappa and lambda FLCs at concentrations as low as 5 and 15 ng/mL, respectively. The mAb-based ELISA has greater sensitivity and reproducibility than does the commercially available immunoturbidimetric assay that uses polyclonal anti-FLC antibodies. In addition, the mAbs can immunostain monoclonal FLC-producing plasma cells and pathologic light chain-related amyloid and nonfibrillar tissue deposits. Our anti-FLC mAbs, with their high degree of reactivity and versatility, may provide an invaluable tool in the diagnosis and management of light chain-associated disease. | 18,854,262 |
A multi-institutional survey of critical diagnoses (critical values) in surgical pathology and cytology. | Critical values (CVs) are well established in clinical pathology, and an analogous concept has recently been suggested in anatomic pathology, with the terminology of critical values, or, alternatively, critical diagnoses (CDs). To better identify anatomic pathology CVs, a survey was sent to 225 members of the Association of Directors of Anatomic and Surgical Pathology (ADASP) for grading 17 possible surgical pathology and 18 possible cytology CVs. There were 73 responses for surgical pathology and 57 for cytology. The majority of the respondents believed in the concept of CVs in anatomic pathology. There was good agreement concerning most of the possible CVs, although there were differences of opinion for some diagnoses. Several additional CVs were suggested, and there was discussion of the best terminology for CVs, degree of urgency, and appropriate notification documentation. A few respondents expressed concern about medicolegal implications. Based on the results of this survey, an ADASP committee has developed national guidelines for CDs (CVs) in surgical pathology and cytology. | 18,854,265 |
Comparison of Russell viper venom-based and activated partial thromboplastin time-based screening assays for resistance to activated protein C. | Thrombotic disease is a significant cause of mortality and morbidity, with an estimated lifetime risk of greater than 10% in Western populations. One of the most common hereditary thrombophilias is the factor V Leiden mutation, which is identified with a screening assay for activated protein C (APC) resistance and confirmed by DNA analysis. In this study, we compared the commercially available Pefakit (Pentapharm, Basel, Switzerland) and Cryocheck (Precision BioLogic, Dartmouth, Canada) assays, 2 recently developed Russell viper venom (RVV)-based screening tests, with the activated partial thromboplastin time (aPTT)-based screening test currently used in our hospital's clinical laboratory. We found that the aPTT-based assay for resistance to APC had a sensitivity of 100%, a specificity of 70%, and a positive predictive value (PPV) of 70%, whereas both of the RVV-based assays exhibited high sensitivity, specificity, and PPV at 100%. In addition, we found that these new functional assays are more cost-effective relative to the screening algorithm previously used in our clinical laboratory and could potentially eliminate the need for DNA analysis, although further study is required. | 18,854,273 |
Value of [18F]fluorodeoxyglucose positron emission tomography in the management of follicular lymphoma: the end of a dilemma? | [18F]Fluorodeoxyglucose (FDG) positron emission tomography (PET) is a powerful tool for the imaging of various lymphomas. Despite its high FDG avidity, there is little data on PET in follicular lymphoma (FL). In this work, we present findings concerning PET at staging and posttreatment evaluation in FL. A total of 181 PET scans were evaluated in 117 patients with FL in a retrospective study. Positron emission tomography-based results were compared with conventional staging in 82 patients. Posttreatment PET evaluation was performed in 99 patients; there were comparable progression-free survivals of PET-positive and PET-negative patients. Positron emission tomography showed more involvement than computed tomography (CT) with clinical examination in 41 of 82 patients (50%), less in 11 of 82 (13%); the same extension was found in 27 of 82 patients (33%), and 3 patients revealed discordant foci visible on PET only and lymphadenopathy without PET activity (P < .001). Including the results of trephine biopsy, PET finally upstaged FL in 15 of 82 patients (18%), which was projected in change of treatment strategy. There were 73 of 99 negative posttreatment PET scans; 54 of 73 PET-negative patients (74%) remain in complete remission (median follow-up, 27 months); 19 (26%) of them relapsed with median of 12 months. Fourteen of 20 (70%) PET-positive patients relapsed with a median of 4.5 months regardless of findings on CT and subsequent therapy. The difference in relapse rates between PET-positive and PET-negative patients is statistically significant (P < .001). Positron emission tomography at staging is able to substantially change treatment strategy in an important proportion of patients with FL. Persisting PET positivity after treatment predicts for a high risk of an early relapse and can identify patients with poor prognosis. | 18,854,283 |
Increased serum tumor markers (CA125 and CA15.3) in primary plasma cell leukemia: a case report and review of the literature. | 73-year-old woman complaining of bone pain and weight loss was suspected to have a malignant disease, and extensive laboratory investigations were carried out. She was diagnosed with multiple myeloma; however, because of the finding of extremely high serum levels of CA125 and CA15.3 and focal liver lesions, a concomitant solid tumor was suspected, which was then excluded with the appropriate tests, including an ultrasound-guided liver biopsy. While being diagnosed, the patient developed a rapidly evolving plasma cell leukemia with a simultaneous increase in CA125 and CA15.3. After treatment with cyclophosphamide and dexamethasone, the peripheral blood plasma cells disappeared and there was a dramatic decrease in the CA125 and CA15.3 tumor markers. High levels of the latter can be observed in patients with aggressive plasma cell dyscrasias, an observation that is crucial in order to avoid unnecessary tests that can result in treatment delay. | 18,854,288 |
Grunting for worms: seismic vibrations cause Diplocardia earthworms to emerge from the soil. | Harvesting earthworms by a practice called 'worm grunting' is a widespread and profitable business in the southeastern USA. Although a variety of techniques are used, most involve rhythmically scraping a wooden stake driven into the ground, with a flat metal object. A common assumption is that vibrations cause the worms to surface, but this phenomenon has not been studied experimentally. We demonstrate that Diplocardia earthworms emerge from the soil within minutes following the onset of grunting. Broadband low frequency (below 500 Hz) pulsed vibrations were present in the soil throughout the area where worms were harvested, and the number of worms emerging decreased as the seismic signal decayed over distance. The findings are discussed in relation to two hypotheses: that worms are escaping vibrations caused by digging foragers and that worms are surfacing in response to vibrations caused by falling rain. | 18,854,292 |
Leukocyte antigen-related protein tyrosine phosphatase negatively regulates hydrogen peroxide-induced vascular smooth muscle cell apoptosis. | Reactive oxygen species (ROS) have been implicated in vascular smooth muscle cell (VSMC) apoptosis, a hallmark of advanced atherosclerotic lesions. Transient oxidation and inactivation of protein-tyrosine phosphatases play a critical role in cellular response to ROS production. However, the function of leukocyte antigen-related (LAR) protein-tyrosine phosphatase in ROS signaling is not known. To determine the expression of LAR in ROS-induced apoptosis, we investigated hydrogen peroxide-induced cell death and signaling in aortic VSMCs from wild-type and LAR(-/-) mice. Histone-associated DNA fragmentation and caspase-3/7 activity were significantly enhanced, mitochondrial membrane integrity was compromised, and cell viability was significantly decreased following H(2)O(2) treatment in LAR(-/-) VSMCs compared with wild-type cells. Stronger and sustained increase in autophosphorylation and activity of Fyn, an Src family tyrosine kinase, was observed in LAR(-/-) cells compared with wild-type cells following H(2)O(2) treatment. LAR binds to activated Fyn in H(2)O(2)-treated VSMCs, and recombinant LAR dephosphorylates phosphorylated-Fyn in vitro. In addition, LAR deficiency enhanced H(2)O(2)-induced phosphorylation of Janus kinase 2 (JAK2), signal transducer and activator of transcription 3 (STAT3), and p38 mitogen-activated protein kinase (MAPK). PP2, a Fyn-specific inhibitor, blocked JAK2, STAT3, and p38 MAPK activation and significantly attenuated apoptosis induced by H(2)O(2). AG490, a JAK2-specific inhibitor, significantly attenuated H(2)O(2)-induced apoptosis, and blocked H(2)O(2)-induced activation of STAT3, but not p38 MAPK in both wild-type and LAR(-/-) VSMCs. Attenuation of Fyn expression by short hairpin RNA significantly decreased H(2)O(2)-induced downstream signaling and apoptosis in VSMCs. Together, these data indicate that LAR regulates Fyn/JAK2/STAT3 and Fyn/p38 MAPK pathways involved in ROS-induced apoptosis. | 18,854,310 |
Screening for deep vein thrombosis in asymptomatic high-risk patients: a comparison between digital photoplethysmography and venous ultrasonography. | To determine the role of digital photoplethysmography in screening asymptomatic patients who are susceptible for developing deep vein thrombosis. Three hundred and thirty-seven limbs in 169 patients who were high risk for development of deep vein thrombosis were assessed by ultrasonography digital photoplethysmography and the results were compared. Thirteen limbs were found to have deep vein thrombosis as demonstrated by ultrasonography. All limbs with a venous refilling time greater than 12 seconds had a normal ultrasonography. Compared with ultrasonography and using refilling time less than 12 seconds as the cutoff point, digital photoplethysmography achieved a sensitivity, specificity, positive predictive value, and negative predictive value of 100%, 73.8%, 13.3%, and 100% respectively, for detecting deep vein thrombosis in asymptomatic high-risk patients. Digital photoplethysmography is a simple, noninvasive, and highly sensitive test for screening of deep vein thrombosis. | 18,854,340 |
The Cohesin loading factor NIPBL recruits histone deacetylases to mediate local chromatin modifications. | Cornelia de Lange Syndrome (CdLS) is a rare congenital malformation disorder. About half of the patients with CdLS carry mutations in the NIPBL gene encoding the NIPBL protein, a subunit of the Cohesin loading complex. Recent studies show association of Cohesin with chromatin-remodeling complexes, either by establishing cohesion or by recruiting Cohesin to specific chromosome locations. In yeast two-hybrid assays, we identified an interaction of NIPBL with the histone deacetylases -1 and -3. These interactions were confirmed in mammalian cells by coimmunoprecipitation and a critical region for interaction was defined to a stretch of 163 amino acids of a highly conserved region of NIPBL, which is mutated in patients with CdLS. Utilizing reporter gene assays, we could show that NIPBL fused to the GAL4-DNA-binding domain (GAL4-DBD) represses promoter activity via the recruitment of histone deacetylases. Interestingly, this effect is dramatically reduced by both NIPBL missense mutations identified in CdLS and by chemical inhibition of the histone deacetylases. Our data are the first to indicate a molecular and functional connection of NIPBL with chromatin-remodeling processes via the direct interaction with histone deacetylases. | 18,854,353 |
Translation affects YoeB and MazF messenger RNA interferase activities by different mechanisms. | Prokaryotic toxin-antitoxin loci encode mRNA cleaving enzymes that inhibit translation. Two types are known: those that cleave mRNA codons at the ribosomal A site and those that cleave any RNA site specifically. RelE of Escherichia coli cleaves mRNA at the ribosomal A site in vivo and in vitro but does not cleave pure RNA in vitro. RelE exhibits an incomplete RNase fold that may explain why RelE requires its substrate mRNA to presented by the ribosome. In contrast, RelE homologue YoeB has a complete RNase fold and cleaves RNA independently of ribosomes in vitro. Here, we show that YoeB cleavage of mRNA is strictly dependent on translation of the mRNA in vivo. Non-translated model mRNAs were not cleaved whereas the corresponding wild-type mRNAs were cleaved efficiently. Model mRNAs carrying frameshift mutations exhibited a YoeB-mediated cleavage pattern consistent with the reading frameshift thus giving strong evidence that YoeB cleavage specificity was determined by the translational reading frame. In contrast, site-specific mRNA cleavage by MazF occurred independently of translation. In one case, translation seriously influenced MazF cleavage efficiency, thus solving a previous apparent paradox. We propose that translation enhances MazF-mediated cleavage of mRNA by destabilization of the mRNA secondary structure. | 18,854,355 |
Prediction of the effect of erythromycin, diltiazem, and their metabolites, alone and in combination, on CYP3A4 inhibition. | Predictive models of complex drug-drug interactions between multiple inhibitors and their metabolites have not been evaluated. The purpose of this study was to evaluate an interaction model for cytochrome P450 3A4 (CYP3A4) that incorporated the simultaneous reversible and irreversible inhibition by multiple inhibitors. Erythromycin (ERY) and diltiazem (DTZ), and their major metabolites, N-desmethylerythromycin (nd-ERY) and N-desmethyldiltiazem (nd-DTZ), were chosen to evaluate the model. k(inact) (rate constant for maximal inactivation), K(I) (inhibitor concentration at 50% maximal inactivation), and K(i) (reversible inhibition constant) were estimated for ERY, DTZ, nd-ERY, and nd-DTZ, respectively, using cDNA-expressed CYP3A4 and human liver microsomes under optimal experimental conditions. To evaluate the interaction model, combinations of inhibitors and metabolites were incubated at concentrations equal to K(I), (1/2)K(I), and 2K(I) of each inhibitor for specified durations in both enzyme systems. The models were further evaluated by the incubation of combinations of inhibitors with the substrate testosterone for 10 min. CYP3A4 inhibition in the presence of drug mixtures was predicted from the inhibition parameters determined for each drug or metabolite alone. The CYP3A4 activity in the presence of multiple inhibitors was well predicted by the model incorporating additive irreversible inhibition as modified by mutual competitive inhibition (percent mean error and percent mean absolute error ranged from -0.06 to 0.04 and from 0.03 to 0.09, respectively). In conclusion, the additive model predicted the combined effect of multiple inhibitors on CYP3A inhibition in vitro. However, simultaneous reversible and irreversible inhibition effects should be taken into account in a reaction mixture of substrate and multiple inhibitors of CYP3A4. | 18,854,379 |
Complement abnormalities in acquired lipodystrophy revisited. | Lipodystrophy is a heterogeneous condition characterized by an inherited or acquired deficiency in the number of adipocytes required for the storage of energy as triglycerides. Acquired lipodystrophy is frequently associated with other autoimmune disorders. One well-studied form is characterized by the selective loss of upper body fat in association with activation of the alternative complement pathway by C3 nephritic factor, low complement factor C3, and mesangiocapillary glomerulonephritis. We now describe an immunologically distinct form of acquired generalized lipodystrophy, with evidence of activation of the classical complement pathway (low C4) and autoimmune hepatitis. Patients and Research Design: Three unrelated patients with acquired lipodystrophy and low complement C4 levels are described. In vitro analysis of the complement pathway was undertaken to determine the reason for the low C4 complement levels. Biopsies were obtained from liver, bone marrow, and adipose tissue for histological analysis. All three patients manifested near-total lipodystrophy, chronic hepatitis with autoimmune features, and low C4 complement levels. Additional autoimmune diseases, including severe hemolytic anemia, autoimmune thyroid disease, and polyneuropathy, were variably present. Detailed studies of complement pathways suggested constitutive classical pathway activation. Although the previously described syndrome, which typically results in a cephalad pattern of partial lipodystrophy, results from activation of the alternative complement pathway, this form, in which lipodystrophy is generalized, is associated with activation of the classical pathway. Future therapeutic approaches to these disorders may benefit from being tailored to their distinct immunopathogenesis. | 18,854,390 |
Acute moderate elevation of TNF-alpha does not affect systemic and skeletal muscle protein turnover in healthy humans. | Skeletal muscle wasting has been associated with elevations in circulating inflammatory cytokines, in particular TNF-alpha. In this study, we investigated whether TNF-alpha affects human systemic and skeletal muscle protein turnover via a 4-h recombinant human (rh) TNF-alpha infusion. We hypothesize that TNF-alpha increases human muscle protein breakdown and/or inhibits synthesis. Using a randomized, controlled, crossover design, postabsorptive healthy young males (n = 8) were studied 2 h under basal conditions followed by a 4-h infusion of either rhTNF-alpha (700 ng . m(-2) . h(-1)) or 20% human albumin (control), which was the vehicle of rhTNF-alpha. Systemic and skeletal muscle protein turnover was estimated by a combination of tracer dilution methodology (primed continuous infusion of l-[ring-(2)H(5)]phenylalanine and l-[(15)N-leucine], with prime of l-[ring-(2)H(4)]tyrosine) and femoral arterial-venous differences over the leg and muscle biopsies. Plasma TNF-alpha concentration rapidly increased from basal levels of approximately 0.7 to 17 pg . ml(-1) with rhTNF-alpha infusion. Whole body protein synthesis, breakdown, and net degradation were similar after the basal and infusion period of the control and rhTNF-alpha trials. Skeletal muscle, musculus vastus lateralis, protein fractional synthetic rate was not different over 4 h of control or rhTNF-alpha (rate of incorporation of (15)N-leucine). Muscle protein turnover determined with the phenylalanine three-compartment model showed similar muscle synthesis, breakdown, and net muscle degradation after 2-h basal and after 4-h control or rhTNF-alpha infusion. This study is the first to show in humans that TNF-alpha does not affect systemic and skeletal muscle protein turnover, when acutely elevated for 4 h to moderate levels not causing adverse effects. | 18,854,397 |
Retinol-binding protein 4 and prediction of incident coronary events in healthy men and women. | Recent studies reported that retinol-binding protein 4 (RBP4) has a causal role in insulin resistance and suggested that its circulating levels may predict cardiovascular disease. However, the latter assumption has not yet been tested. We assessed the value of RBP4 measurement in the prediction of incident coronary artery disease (CAD). We conducted a nested case-control study of incident CAD (n = 1036 cases vs. n = 1889 controls) selected from among 25,336 participants of the EPIC-Norfolk study. Healthy men and women, aged between 45 and 79 yr, were recruited from age-sex registers of general practices in Norfolk. Participants completed a baseline questionnaire survey between 1993 and 1997, attended a clinic visit, and were followed for an average of 6 yr. Cases (n = 1036) were participants who developed CAD during the follow-up. Controls (n = 1889) matched by age, sex, and enrollment time remained free of any CAD during follow-up. Risk of incident fatal or nonfatal CAD according to RBP4 quartiles was assessed. RBP4 levels were higher in cases than in controls. RBP4 levels correlated weakly with body mass index, waist-to-hip ratio, systolic and diastolic blood pressure, and total and low-density lipoprotein-cholesterol and were inversely associated with C-reactive protein concentrations. The strongest correlation was found with triglycerides. The risk of incident CAD was associated with increasing quartiles of RBP4 levels (P = 0.03). However, adjustment for cardiovascular risk factors abolished this association. Measurement of serum RBP4 does not provide added value for predicting CAD risk beyond traditional risk factors. | 18,854,400 |
Decidual vascularization and the expression of angiogenic growth factors and proteases in first trimester spontaneous abortions. | Decidual vascular development is important for implantation. This study analysed decidual vascular adaptation to implantation in correlation with miscarriage in decidual secretory endometrium (DSE), decidua parietalis (DP) and decidua basalis (DB) of miscarriage patients and matched controls. Decidua was obtained during first trimester termination of pregnancy (controls) and vacuum aspiration in case of missed abortion (cases). Vascularization and the expression of VEGF-A, placental growth factor, Flt-1, KDR, angiopoietin (Ang)-1, Ang-2, TIE-2, and membrane-type matrix metalloproteinases MT1-, MT2-, MT3- and MT5-MMP were determined at mRNA and protein level. Uterine natural killer cells (CD56), macrophages (CD68), proliferation (Ki67) and apoptosis (activated caspase-3) were evaluated in consecutive sections. Decidual vascularization showed differences between cases and controls, i.e. fewer vessels with larger circumference in cases. This correlated with the differential expressions of various factors at mRNA/antigen level and with increased endothelial flt1, KDR, MT2- and MT5-MMP expression in miscarriage patients. The differences between cases and controls were probably not based on altered proliferation and/or apoptosis, since Ki67 and active Caspase-3 showed comparable expression levels in both groups. Although DB of cases and controls showed similar amounts of CD56- and CD68-positive cells, the case group did show elevated levels of CD56 in DSE (P < 0.05) and of CD68 in DP compared with the control group (P < 0.05). The differences in vascularization and in the expression of angiogenic factors and proteases between groups suggest a correlation between decidual vascularization and the occurrence of miscarriages. | 18,854,409 |
Measuring the effectiveness of protected area networks in reducing deforestation. | Global efforts to reduce tropical deforestation rely heavily on the establishment of protected areas. Measuring the effectiveness of these areas is difficult because the amount of deforestation that would have occurred in the absence of legal protection cannot be directly observed. Conventional methods of evaluating the effectiveness of protected areas can be biased because protection is not randomly assigned and because protection can induce deforestation spillovers (displacement) to neighboring forests. We demonstrate that estimates of effectiveness can be substantially improved by controlling for biases along dimensions that are observable, measuring spatial spillovers, and testing the sensitivity of estimates to potential hidden biases. We apply matching methods to evaluate the impact on deforestation of Costa Rica's renowned protected-area system between 1960 and 1997. We find that protection reduced deforestation: approximately 10% of the protected forests would have been deforested had they not been protected. Conventional approaches to evaluating conservation impact, which fail to control for observable covariates correlated with both protection and deforestation, substantially overestimate avoided deforestation (by over 65%, based on our estimates). We also find that deforestation spillovers from protected to unprotected forests are negligible. Our conclusions are robust to potential hidden bias, as well as to changes in modeling assumptions. Our results show that, with appropriate empirical methods, conservation scientists and policy makers can better understand the relationships between human and natural systems and can use this to guide their attempts to protect critical ecosystem services. | 18,854,414 |
Pycnogenol, an extract from French maritime pine, suppresses Toll-like receptor 4-mediated expression of adipose differentiation-related protein in macrophages. | Adipose differentiation-related protein (ADRP) is highly expressed in macrophages and human atherosclerotic lesions. We demonstrated that Toll-like receptor (TLR) 4-mediated signals, which are involved in atherosclerosis formation, enhanced the expression of ADRP in macrophages. Lipopolysaccharide (LPS) enhanced the ADRP expression in RAW264.7 cells or peritoneal macrophages from wild-type mice, but not in macrophages from TLR4-deficient mice. Actinomycin D almost completely abolished the LPS effect, whereas cycloheximide decreased the expression at 12 h, indicating that the LPS-induced ADRP expression was stimulated at the transcriptional level and was also mediated by new protein synthesis. LPS enhanced the ADRP promoter activity, in part, by stimulating activator protein (AP)-1 binding to the Ets/AP-1 element. In addition, preceding the increase of the ADRP mRNA, LPS induced the expression of interleukin (IL)-6, IL-1alpha, and interferon-beta mRNAs, all of which stimulated the ADRP expression. Antibodies against these cytokines or inhibitors of c-Jun NH(2)-terminal kinase and nuclear factor (NF)-kappaB suppressed the ADRP mRNA level. Thus TLR4 signals stimulate the ADRP expression both in direct and indirect manners. Pycnogenol (PYC), an extract of French maritime pine, suppressed the expression of ADRP and the above-mentioned cytokines. PYC suppressed the ADRP promoter activity and enhancer activity of AP-1 and NF-kappaB, whereas it did not affect the LPS-induced DNA binding of these factors. In conclusion, TLR4-mediated signals stimulate the ADRP expression in macrophages while PYC antagonizes this process. PYC, a widely used dietary supplement, might be useful for prevention of atherosclerosis. | 18,854,426 |
Comparison of eye lens dose on neuroimaging protocols between 16- and 64-section multidetector CT: achieving the lowest possible dose. | To our knowledge, there has been no study that compares the radiation dose delivered to the eye lens by 16- and 64-section multidetector CT (MDCT) for standard clinical neuroimaging protocols. Our aim was to assess radiation-dose differences between 16- and 64-section MDCT from the same manufacturer, by using near-identical neuroimaging protocols. Three cadaveric heads were scanned on 16- and 64-section MDCT by using standard neuroimaging CT protocols. Eye lens dose was measured by using thermoluminescent dosimeters (TLD), and each scanning was repeated to reduce random error. The dose-length product, volume CT dose index (CTDI(vol)), and TLD readings for each imaging protocol were averaged and compared between scanners and protocols, by using the paired Student t test. Statistical significance was defined at P < .05. The radiation dose delivered and eye lens doses were lower by 28.1%-45.7% (P < .000) on the 64-section MDCT for near-identical imaging protocols. On the 16-section MDCT, lens dose reduction was greatest (81.1%) on a tilted axial mode, compared with a nontilted helical mode for CT brain scans. Among the protocols studied, CT of the temporal bone delivered the greatest radiation dose to the eye lens. Eye lens radiation doses delivered by the 64-section MDCT are significantly lower, partly due to improvements in automatic tube current modulation technology. However, where applicable, protection of the eyes from the radiation beam by either repositioning the head or tilting the gantry remains the best way to reduce eye lens dose. | 18,854,441 |
Occipital intradiploic CSF pseudocyst: an unusual complication of a ventriculoperitoneal shunt malfunction. | We report a rare and unique complication of ventriculoperitoneal (VP) shunt malfunction. A progressively expansile, CSF-containing occipital intradiploic cyst developed in a 15-year-old boy at the site of cystoperitoneal shunt draining a Dandy-Walker cyst; the shunt was placed when the boy was 4 years old. A proposed pathogenesis of the lesion is discussed. | 18,854,442 |
First demonstration of cerebrospinal fluid and plasma A beta lowering with oral administration of a beta-site amyloid precursor protein-cleaving enzyme 1 inhibitor in nonhuman primates. | beta-Site amyloid precursor protein (APP)-cleaving enzyme (BACE) 1 cleavage of amyloid precursor protein is an essential step in the generation of the potentially neurotoxic and amyloidogenic A beta 42 peptides in Alzheimer's disease. Although previous mouse studies have shown brain A beta lowering after BACE1 inhibition, extension of such studies to nonhuman primates or man was precluded by poor potency, brain penetration, and pharmacokinetics of available inhibitors. In this study, a novel tertiary carbinamine BACE1 inhibitor, tertiary carbinamine (TC)-1, was assessed in a unique cisterna magna ported rhesus monkey model, where the temporal dynamics of A beta in cerebrospinal fluid (CSF) and plasma could be evaluated. TC-1, a potent inhibitor (IC(50) approximately 0.4 nM), has excellent passive membrane permeability, low susceptibility to P-glycoprotein transport, and lowered brain A beta levels in a mouse model. Intravenous infusion of TC-1 led to a significant but transient lowering of CSF and plasma A beta levels in conscious rhesus monkeys because it underwent CYP3A4-mediated metabolism. Oral codosing of TC-1 with ritonavir, a potent CYP3A4 inhibitor, twice daily over 3.5 days in rhesus monkeys led to sustained plasma TC-1 exposure and a significant and sustained reduction in CSF sAPP beta, A beta 40, A beta 42, and plasma A beta 40 levels. CSF A beta 42 lowering showed an EC(50) of approximately 20 nM with respect to the CSF [TC-1] levels, demonstrating excellent concordance with its potency in a cell-based assay. These results demonstrate the first in vivo proof of concept of CSF A beta lowering after oral administration of a BACE1 inhibitor in a nonhuman primate. | 18,854,490 |
Seasonal and regional short-term effects of fine particles on hospital admissions in 202 US counties, 1999-2005. | The authors investigated whether short-term effects of fine particulate matter with an aerodynamic diameter < or =2.5 microm (PM(2.5)) on risk of cardiovascular and respiratory hospitalizations among the elderly varied by region and season in 202 US counties for 1999-2005. They fit 3 types of time-series models to provide evidence for 1) consistent particulate matter effects across the year, 2) different particulate matter effects by season, and 3) smoothly varying particulate matter effects throughout the year. The authors found statistically significant evidence of seasonal and regional variation in estimates of particulate matter effect. Respiratory disease effect estimates were highest in winter, with a 1.05% (95% posterior interval: 0.29, 1.82) increase in hospitalizations per 10-microg/m(3) increase in same-day PM(2.5). Cardiovascular diseases estimates were also highest in winter, with a 1.49% (95% confidence interval: 1.09, 1.89) increase in hospitalizations per 10-microg/m(3) increase in same-day PM(2.5), with associations also observed in other seasons. The strongest evidence of a relation between PM(2.5) and hospitalizations was in the Northeast for both respiratory and cardiovascular diseases. Heterogeneity of PM(2.5) effects on hospitalizations may reflect seasonal and regional differences in emissions and in particles' chemical constituents. Results can help guide development of hypotheses and further epidemiologic studies on potential heterogeneity in the toxicity of constituents of the particulate matter mixture. | 18,854,492 |
The impact of a large reduction in the price of alcohol on area differences in interpersonal violence: a natural experiment based on aggregate data. | This paper examines the effect of a drastic reduction in the price of alcohol that occurred in Finland in 2004 on interpersonal violence in the Helsinki Metropolitan Area, and how these changes varied at the small-area level. This study comprised 86 administrative tracts from the Helsinki Metropolitan Area. Data pertaining to the social structure of the tracts and interpersonal violence were collected from archival sources in the cities and the police in 2002-2005, and analysed using regression analysis. Interpersonal violence rates did not increase after a large reduction in alcohol prices and an increase in consumption. For domestic violence, the rate even decreased. There was a significant relationship between measures of social disadvantage and interpersonal violence. A low educational level and a high outmigration level were the most salient factors. The differences in impact of the reduction in alcohol prices on interpersonal violence between high-, intermediate- and low-status areas were small. It would appear that a radical reduction in the price of alcohol and an increase in consumption do not necessarily lead to detrimental consequences in interpersonal violence or to an adverse development in areas of social disadvantage. | 18,854,505 |
Pyridoxine-dependent seizures caused by alpha amino adipic semialdehyde dehydrogenase deficiency: the first polish case with confirmed biochemical and molecular pathology. | Pyridoxine-dependent seizures are a rare condition recognized when numerous seizures respond to pyridoxine treatment and recur on pyridoxine withdrawal. For decades the diagnosis was confirmed only with pyridoxine treatment withdrawal trial. Recently described biochemical and molecular pathology improved the diagnostic process for those cases in which seizures are caused by alpha amino adipic semialdehyde dehydrogenase deficiency. This article presents a girl with recurrent status epilepticus episodes resistant to phenobarbital and phenytoin and partly responding to midazolam. Eventually the seizures were completely controlled with pyridoxine; however, due to the severe condition of this child when seizing, no trial of withdrawal has been performed. The diagnosis of pyridoxine-dependent seizures was confirmed with biochemical and molecular testing revealing elevated alpha-AASA excretion and the presence of 2 different mutations in the antiquitin ( ALDH7A1) gene. Due to the availability of reliable laboratory testing, confirmation of the diagnosis was made without the life-threatening trial of pyridoxine withdrawal. | 18,854,520 |
Automated image analysis of cytokinesis-blocked micronuclei: an adapted protocol and a validated scoring procedure for biomonitoring. | Micronuclei (MN) frequencies in peripheral blood lymphocytes have been used worldwide as a biomarker of chromosomal damage for genotoxicity testing and biomonitoring studies. Automation of MN analysis would provide faster and more reliable results with minimizing subjective MN identification. We developed an automated facility for the scoring of the in vitro MN cytokinesis-block assay for biomonitoring on Giemsa-stained slides, fulfilling the following criteria: applicable to the cytokinesis-block micronucleus methodology, discriminating between mono-, bi- and polynucleated cells, MN scoring according to HUMN scoring criteria, false-negative MN rate <10% and false-positive (FP) MN rate <1%. We first adapted the slide preparation protocol to obtain an optimal cell density and dispersion, which is important for image analysis. We developed specific algorithms starting from the cell as a detection unit. The whole detection and scoring process was separated into two distinct steps: in the first step, the cells and nuclei are detected; then, in the second step, the MN are searched for in the detected cells. Since the rate of FP MN obtained by the automatic analysis was in the range of 0.5-1.5%, an interactive visual validation step was introduced, which is not time consuming and allows quality control. Validation of the automated scoring procedure was undertaken by comparing the results of visual and automated scoring of micronucleated mono- and binucleated cells in human lymphocytes induced by two clastogens (ionizing radiation and methyl methane-sulphonate), two aneugens (nocodazole and carbendazim) and one apoptogen (staurosporine). Although the absolute MN frequencies obtained with automated scoring were lower as compared to those detected by visual scoring, a clear dose response for MNBN frequencies was observed with the automated scoring system, indicating that it is able to produce biologically relevant and reliable results. These observations, together with its ability to detect cells, nuclei and MN in accordance with the HUMN scoring criteria, confirm the usability of the automated MN analysis system for biomonitoring. | 18,854,579 |
Genetics of mating and sex determination in the parasitic nematode Haemonchus contortus. | Genetic analysis of parasitic nematodes has been a neglected area of research and the basic genetics of this important group of pathogens are poorly understood. Haemonchus contortus is one of the most economically significant livestock parasites worldwide and is a key experimental model for the strongylid nematode group that includes many important human and animal pathogens. We have undertaken a study of the genetics and the mode of mating of this parasite using microsatellite markers. Inheritance studies with autosomal markers demonstrated obligate dioecious sexual reproduction and polyandrous mating that are reported here for the first time in a parasitic helminth and provide the parasite with a mechanism of increasing genetic diversity. The karyotype of the H. contortus, MHco3(ISE) isolate was determined as 2n = 11 or 12. We have developed a panel of microsatellite markers that are tightly linked on the X chromosome and have used them to determine the sex chromosomal karyotype as XO male and XX female. Haplotype analysis using the X-chromosomal markers also demonstrated polyandry, independent of the autosomal marker analysis, and enabled a more direct estimate of the number of male parental genotypes contributing to each brood. This work provides a basis for future forward genetic analysis on H. contortus and related parasitic nematodes. | 18,854,587 |
The effect of third harmonic transmit phasing on contrast agent responses for CTR improvement. | Harmonic detection of ultrasonic contrast agents provides a limited contrast-to-tissue ratio (CTR) mainly because of background tissue harmonic signals. To suppress tissue harmonic amplitude, the method of third harmonic (3f(0)) transmit phasing can be utilized by phasing an additional 3f(0) transmit signal to achieve effective cancellation between the frequency-sum component and the frequency-difference component of the tissue harmonic signal. For contrast agents, on the other hand, our results indicate that the nonlinear responses from microbubbles behave very differently in 3f(0) transmit phasing. Specifically, the suppression phase for the contrast microbubble deviates from that for tissue. Moreover, the achievable suppression of the contrast harmonic signal is markedly reduced. Consequently, with the selection of 3f(0) transmit phase that leads to maximal tissue suppression, the CTR can be optimally improved in harmonic imaging. Nevertheless, the CTR improvement in 3f(0) transmit phasing can be compromised when the tissue suppression decreases in the presence of spectral leakage. Consequently, multi-pulse sequences such as pulse inversion are suggested for leakage removal in 3f(0) transmit phasing. | 18,854,607 |
Characterization of a scintillating GEM detector with low energy x-rays. | A two-dimensional position-sensitive dosimetry system based on a scintillating gas detector is being developed with the aim of using it for pre-treatment verification of dose distributions in charged particle therapy. The dosimetry system consists of a chamber filled with an Ar/CF(4) scintillating gas mixture, inside which two cascaded gas electron multipliers (GEMs) are mounted. A GEM is a thin kapton foil with copper cladding structured with a regular pattern of sub-mm holes. In such a system, light quanta are emitted by the scintillating gas mixture during the electron avalanches in the GEM holes when radiation traverses the detector. The light intensity distribution is proportional to the energy deposited in the detector's sensitive volume by the beam. In the present work, we investigated the optimization of the scintillating GEM detector light yield. The light quanta are detected by means of a CCD camera or a photomultiplier tube coupled to a monochromator. The GEM charge signal is measured simultaneously. We have found that with 60 microm diameter double conical GEM holes, a brighter light signal and a higher electric signal are obtained than with 80 microm diameter holes. With an Ar + 8% CF(4) volume concentration, the highest voltage across the GEMs and the largest light and electric signals were reached. Moreover, we have found that the emission spectrum of Ar/CF(4) is independent of (1) the voltages applied across the GEMs, (2) the x-ray beam intensity and (3) the GEM hole diameter. On the other hand, the ratio of Ar to CF(4) peaks in the spectrum changes when the concentration of the latter gas is varied. | 18,854,612 |
Simple analytical expressions for the dose of point photon sources in homogeneous media. | The contributions to the dose of a point photon source in homogeneous media due to primary and first, second, ..., nth scattered photons are investigated. Assuming a simple statistical model, an analytical form comes out for each of these contributions. It includes a polynomial and a single exponential and depends on three parameters which have a physical meaning. The values of these parameters for different energies and for water, as a test case, are obtained from numerical fits to the results of a Monte Carlo simulation with the code PENELOPE. The average differences between the model and the Monte Carlo results, after the fitting process, are below 1%. Our model permits to obtain improved versions of the classical approach of Berger in a straightforward way. The expressions obtained also describe the dose build-up of the primary photons. | 18,854,613 |
Clinical utility of evaluating intracranial artery stenosis and silent brain infarction to predict the presence of subclinical coronary artery disease in ischemic stroke patients. | We have recently reported the prevalence of subclinical cardiovascular diseases and the association between the presence of subclinical coronary artery disease (CAD) and vascular risk factors in ischemic stroke patients. The relationship between the presence of subclinical CAD and elements of brain ischemia including intracranial artery stenosis, silent brain infarction (SBI), and white matter lesions remains unclear. We determined the usefulness of elements of brain ischemia to predict the presence of subclinical CAD in ischemic stroke patients. The study group comprised 100 patients with first-ever ischemic stroke who had no history of CAD. Intracranial artery stenosis on magnetic resonance angiography and SBI and white matter lesions on magnetic resonance imaging were investigated in comparison with CAD defined as > or =50% stenosis on coronary computed tomographic angiography. Thirty-six patients had subclinical CAD. Intracranial artery stenosis (78.1% vs 35.1%, p<0.0001) and SBI (69.4% vs 46.9%, p=0.03) were more prevalent in patients with subclinical CAD. Of the patients with both intracranial artery stenosis and SBI, 61% had subclinical CAD. Multiple regression analyses showed that the presence of subclinical CAD was independently associated with intracranial artery stenosis; <50% stenosis (OR 8.01 95%CI 2.02 to 31.9; p<0.01), > or =50% stenosis (OR 19.5 95%CI 2.77 to 137.4; p<0.01), and multiple SBI (OR 3.85 95%CI 1.23 to 12.0; p<0.05). The evaluation of intracranial artery stenosis and SBI may be useful to identify ischemic stroke patients at high risk for subclinical CAD. | 18,854,628 |
Survey on the handling of chronic obstructive pulmonary disease by annual health check in Japan. | Since mild COPD can be detected in the annual health check by lung function tests, we conducted a questionnaire survey on how such examinations are used to assess chronic obstructive pulmonary disease (COPD). We mailed questionnaires to 633 facilities performing comprehensive medical check-up from June to July 2005 and obtained responses from 254 (40.1%). At participating facilities, the proportion of full or part-time physicians specializing in respiratory diseases was low [40 of 366 full timers (10.9%) and 114 of 2,044 part-timers (5.6%)], with very few physicians certified by the Japanese Respiratory Society (6.8%). Non respiratory physicians were involved in evaluating the results of thoracic diagnostic imaging at 32 facilities. Lung function tests were carried out at 98.2% of facilities though relatively few facilities evaluated test results with COPD in mind. All stages (mild, moderate, severe) of COPD were diagnosed in patients at 85 facilities (39.2%), while only severe COPD was targeted by chest imaging at 97 facilities (44.7%), disregarding mild and moderate cases. Counseling for smoking cessation was provided at 113 facilities (20.6%), while 30 facilities (14.4%) provided no form of smoking cessation. At most facilities performing a comprehensive medical check-up, there was not a sufficient number of respirologists to ensure early diagnosis of COPD and this may have compromised COPD diagnosis. The newly proposed Japan Society of Comprehensive Medical Check-up (Ningen-dock) Standards based on the Japanese Respiratory Society may be useful to reveal early stages of COPD. | 18,854,630 |
Endoscopic removal of an accidentally swallowed toothbrush. | A rare case is reported with a large foreign body in the upper gastrointestinal tract. A 19-year-old girl accidentally swallowed her toothbrush which was successfully removed via endoscopy using a polypectomy snare under topical pharyngeal anesthesia. The extracted toothbrush was 20 cm long, and it had the characteristic radiographic image. | 18,854,631 |
Left ventricular oozing rupture following acute myocardial infarction. | We describe the case of an 85-year-old woman in whom pericardiocentesis, prolonged bed rest and blood pressure control were performed without surgery to successfully treat an oozing-type myocardial rupture due to myocardial infarction. | 18,854,633 |
Palliative radiotherapy of retrobulbar orbit metastases due to breast cancer. | In breast cancer, the occurrence of retrobulbar metastases of the orbit is rare compared to intraocular metastases. The clinical symptoms are quite different. Impairment of vision, exophthalmus, double vision, vertigo, and pain reduce patients' quality of life. The benefit of palliative irradiation of the orbit was researched retrospectively in 7 patients. This report also presents the first case in the literature of a breast cancer patient with bi-orbital enophthalmus caused by bilateral retrobulbar metastases that were successfully treated with radiotherapy. Irradiation was performed by photon or electron beams (20-50 Gy). Clinical restaging was done at the end of radiotherapy and 6 weeks thereafter. After irradiation, 6 out of 7 patients showed a distinct clinical response with good palliation and no major side effects. Exophthalmus, pain, and vertigo were significantly reduced in all cases. Double vision disappeared in 3 out of 4 patients, eye muscle paralysis in 5 out of 6 patients. The median overall survival after irradiation of the orbit was 7.3 months. Palliative radiotherapy of retrobulbar metastases of breast cancer is very effective in reducing acute clinical symptoms and increasing quality of life. Nonetheless, patients have a poor prognosis. | 18,854,652 |
Hypertension and the eye. | This article reviews the findings of systemic hypertension in the eye and how these changes represent disease in the eye itself, as well as the predictive value of fundoscopic findings in relation to overall health. Systemic hypertension is associated with observable changes in the retinal microvasculature, including retinopathy, choroidopathy and optic neuropathy, as well as with an increased risk of ocular vascular abnormalities such as arterial and venous occlusive disease, retinal arteriolar macroaneurysm formation and embolic events. Hypertension also confers increased risk for development and progression of diabetic retinopathy, glaucoma and age-related macular degeneration. Grading systems have been proposed that attempt to correlate observed ocular hypertensive changes with systemic vascular disease severity, morbidity and mortality. The widespread availability of digital imaging systems and computer analysis along with revised grading systems has enabled a more precise and reliable examination. This has renewed the interest in the use of routine fundoscopic screening for patients with hypertension in an effort to identify microvascular changes that may provide prognostic information for cardiovascular risk stratification and disease progression. Identification of early microvascular changes on fundoscopic examination using reliable and reproducible imaging techniques may become an important and routine screening modality for the prevention and management of both the ocular and systemic complications of hypertension. | 18,854,694 |
The eye and thyroid disease. | The pathophysiology and optimal management of thyroid eye disease (TED) have not yet been elucidated. Recent studies have increased our knowledge of the disease process and different diagnostic and therapeutic options. This review highlights the recent progress in TED research and identifies areas requiring further advancements. The pathophysiology of TED likely involves genetic and environmental factors, which may potentiate cellular and humoral-mediated inflammation within the orbit. Despite progress in TED research, a target antigen has not been established with certainty. New diagnostic methods and questionnaires are being developed that potentially provide information regarding inflammatory activity of TED. Corticosteroids alone or in combination with orbital radiation may be effective in improving TED symptoms. New immunomodulating therapies may also have a role TED management. Surgery is highly effective for treatment of TED-induced optic nerve compression and for managing the chronic soft tissue changes of TED. A unifying hypothesis of TED pathophysiology is elusive. Further bench research into the autoimmune process is needed. In addition, large, prospective, randomized clinical trials based on the inflammatory activity of disease, while difficult to design, are essential to develop a consensus regarding the proper timing and use of anti-inflammatory medications. | 18,854,695 |
Observational studies analyzed like randomized experiments: an application to postmenopausal hormone therapy and coronary heart disease. | The Women's Health Initiative randomized trial found greater coronary heart disease (CHD) risk in women assigned to estrogen/progestin therapy than in those assigned to placebo. Observational studies had previously suggested reduced CHD risk in hormone users. Using data from the observational Nurses' Health Study, we emulated the design and intention-to-treat (ITT) analysis of the randomized trial. The observational study was conceptualized as a sequence of "trials," in which eligible women were classified as initiators or noninitiators of estrogen/progestin therapy. The ITT hazard ratios (HRs) (95% confidence intervals) of CHD for initiators versus noninitiators were 1.42 (0.92-2.20) for the first 2 years, and 0.96 (0.78-1.18) for the entire follow-up. The ITT HRs were 0.84 (0.61-1.14) in women within 10 years of menopause, and 1.12 (0.84-1.48) in the others (P value for interaction = 0.08). These ITT estimates are similar to those from the Women's Health Initiative. Because the ITT approach causes severe treatment misclassification, we also estimated adherence-adjusted effects by inverse probability weighting. The HRs were 1.61 (0.97-2.66) for the first 2 years, and 0.98 (0.66-1.49) for the entire follow-up. The HRs were 0.54 (0.19-1.51) in women within 10 years after menopause, and 1.20 (0.78-1.84) in others (P value for interaction = 0.01). We also present comparisons between these estimates and previously reported Nurses' Health Study estimates. Our findings suggest that the discrepancies between the Women's Health Initiative and Nurses' Health Study ITT estimates could be largely explained by differences in the distribution of time since menopause and length of follow-up. | 18,854,702 |
Emergence of Asiatic Vibrio diseases in South America in phase with El Niño. | The seventh pandemic of Vibrio cholerae unexpectedly reached the coast of Peru in 1991, causing an explosive emergence of infections throughout the American continents. The origin and routes of dissemination are as yet unknown. A new Vibrio epidemic arose in 1997 in South America (northern Chile) when the pandemic clone of Vibrio parahaemolyticus was for the fist time detected outside of Asia. These 2 cases were concurrent with 2 episodes of El Niño. We carried out a survey of records of V. parahaemolyticus infection and of strains existing in the Instituto Nacional de Salud of Peru between 1994 and 2005. Association between the El Niño event and the V. parahaemolyticus disease was analyzed through generalized additive models applied to time-series data with negative binomial response, selecting some oceanographic factors distinctive of the movement of the El Niño waters. Epidemiologic data and laboratory investigations of the strains showed that V. parahaemolyticus infections caused by the pandemic clone emerged in the coasts of Peru linked to the 1997 El Niño episode. The epidemic dissemination of this clone matched the expansion and dynamics of the poleward propagation and the receding of the El Niño waters. This pattern was similar to previously reported onset of cholera epidemic in 1991. These findings identify the El Niño episodes as a reliable vehicle for the introduction and propagation of Vibrio pathogens in South America. The movement of oceanic waters seems to be one of the driving forces of the spread of Vibrio diseases. | 18,854,707 |
Self-reported and measured sleep duration: how similar are they? | Recent epidemiologic studies have found that self-reported duration of sleep is associated with obesity, diabetes, hypertension, and mortality. The extent to which self reports of sleep duration are similar to objective measures and whether individual characteristics influence the degree of similarity are not known. Eligible participants at the Chicago site of the Coronary Artery Risk Development in Young Adults Study were invited to participate in a 2003-2005 ancillary sleep study; 82% (n = 669) agreed. Sleep measurements collected in 2 waves included 3 days each of wrist actigraphy, a sleep log, and questions about usual sleep duration. We estimate the average difference and correlation between subjectively and objectively measured sleep by using errors-in-variables regression models. Average measured sleep was 6 hours, whereas the average from subjective reports was 6.8 hours. Subjective reports increased on average by 34 minutes for each additional hour of measured sleep. Overall, the correlation between reported and measured sleep duration was 0.47. Our model suggests that persons sleeping 5 hours over-reported their sleep duration by 1.2 hours, and those sleeping 7 hours over-reported by 0.4 hours. The correlations and average differences between self-reports and measured sleep varied by health, sociodemographic, and sleep characteristics. In a population-based sample of middle-aged adults, subjective reports of habitual sleep are moderately correlated with actigraph-measured sleep, but are biased by systematic over-reporting. The true associations between sleep duration and health may differ from previously reported associations between self-reported sleep and health. | 18,854,708 |
Assessing the efficacy of 2 years of maintenance treatment with venlafaxine extended release 75-225 mg/day in patients with recurrent major depression: a secondary analysis of data from the PREVENT study. | The objective of this study was to evaluate the long-term efficacy of venlafaxine extended release (ER) < or =225 mg/day in patients with recurrent major depressive disorder (MDD). In this double-blind trial, outpatients with recurrent MDD (N=1096) were randomized to 10 weeks of acute-phase treatment with venlafaxine ER (75-300 mg/day) or fluoxetine (20-60 mg/day) followed by a 6-month continuation phase and two consecutive 12-month maintenance phases. At the start of each maintenance period, venlafaxine ER responders were randomized to double-blind venlafaxine ER or placebo. In this analysis, data from responders to acute and continuation treatment were analyzed during the combined maintenance phases while receiving venlafaxine ER < or =225 mg/day. Failure to maintain response was defined as an increase in maintenance dose to 300 mg/day or recurrence. Differences were calculated using Kaplan-Meier methods and compared using log-rank tests. Continuation-phase responders (n=114) receiving venlafaxine ER < or =225 mg/day comprised the analysis population (venlafaxine ER: n=55; placebo: n=59). The estimated probability for remaining well across 24 months of maintenance treatment was 67% for venlafaxine ER and 41% for placebo (P=0.007). Venlafaxine ER effectively maintained response at doses < or =225 mg/day for up to 2.5 years in patients with recurrent MDD. The findings are consistent with those of the full data set. | 18,854,724 |
Blood vessel contributions to retinal nerve fiber layer thickness profiles measured with optical coherence tomography. | To understand better the influence of retinal blood vessels (BVs) on the interindividual variation in the retinal nerve fiber layer (RNFL) thickness measured with optical coherence tomography (OCT). RNFL thickness profiles were measured by OCT in 16 control individuals and 16 patients. The patients had advanced glaucoma defined by abnormal disc appearance, abnormal visual fields, and a mean visual field deviation worse than -10 dB. In general, the OCT RNFL thickness profiles showed 4 local maxima, with the peak amplitudes in the superior and inferior regions occurring in the temporal (peripapillary) disc region. There was considerable variability among individuals in the location of these maxima. However, the 4 maxima typically fell on, or near, a major BV with the temporal and inferior peaks nearly always associated with the main temporal branches of the superior and inferior veins and arteries. In the patients' hemifields with severe loss (mean visual field deviation worse than -20 dB), the signals associated with the major BVs were in the order of 100 to 150 microm. The variation in the local peaks of the RNFL profiles of controls correlates well with the location of the main temporal branches of the superior and inferior veins and arteries. This correspondence is, in part, due to a direct BV contribution to the shape of the OCT RNFL and, in part, due to the fact that BVs develop along the densest regions of axons. Although the overall BV contribution was estimated to be relatively modest, roughly 13% of the total peripapillary RNFL thickness in controls, their contribution represents a substantial portion locally and increases in importance with disease progression. | 18,854,727 |
Adult onset buphthalmos in a patient with marfan syndrome. | To report a Marfan patient with an adult onset of buphthalmos. Observational case report. Review of clinical, photographic, and ultrasound data of a 20-year-old Marfan patient who underwent an intraocular lens implantation complicated by late retinal detachment, chronic hyphema, and elevated intraocular pressure (IOP). A 6-month period of IOP between 25 and 30 mm Hg resulted in a 3.75 mm increase in axial length, a 1-mm increase in corneal diameter, and a 2 mm increase in exophthalmos. Buphthalmos secondary to long-term ocular hypertension can occur in an adult patient with Marfan syndrome presumably because of abnormal collagen structure. Thus, Marfan patients with high IOP should be treated aggressively to avoid optic nerve damage and other anatomic and structural changes. | 18,854,734 |
Increased Long-term measurement variability with scanning laser polarimetry employing enhanced corneal compensation: an early sign of glaucoma progression. | To investigate whether the intervisit standard deviation (ISD) of various scanning laser polarimetry parameters is increased, in progressing glaucoma. GDx-variable corneal compensation (VCC) and GDx-enhanced corneal compensation (ECC) measurements, and Octopus G2 visual field tests, were performed at 6-month intervals on 27 healthy subjects and 52 consecutive glaucoma patients. One eye per participant was analyzed. Fifteen patients progressed (on the basis of visual field criteria) and 37 remained stable, during the 2.6+/-0.4 years follow-up. Baseline visual field indices and the stage of glaucoma did not differ between the glaucoma groups. No regression with time was found for any GDx parameter in any group. The ISD of GDx-ECC nerve fiber indicator (NFI), but not GDx-VCC NFI, was significantly higher in progression than in the stable glaucoma group (Mann-Whitney U test with Bonferroni correction, P=0.028). Also, several other ISD values tended to increase in the progressing group. Logistic regression analysis revealed that ISD of NFI [odds ratio (OR)=1.22, P=0.013], inferior average (OR=1.80, P=0.035), and average thickness along the measuring ellipse (OR=2.00, P=0.042), as determined with GDx-ECC (but not with GDx-VCC), all associated with visual field progression, independently of patient age. With GDx-ECC, increase of ISD is an early sign of glaucoma progression, precedes the development of detectable parameter changes, and is associated with visual field progression. | 18,854,736 |
Long-term comparison of primary trabeculectomy with 5-fluorouracil versus mitomycin C in West Africa. | To compare the long-term efficacy and safety of intraoperative 5-fluorouracil (5-FU) versus mitomycin-C (MMC) used adjunctively with primary trabeculectomy in a Black West African population. Retrospective comparative study supplemented with cross-sectional follow-up data. Review of 68 eyes of 68 Black West African subjects that underwent primary trabeculectomy with the use of intraoperative 5-FU or MMC between January 1, 1988 and January 1, 2002 and had at least 3 years postoperative follow-up. Postoperative outcome measures included intraocular pressure (IOP) control, number of glaucoma medications, visual acuity, and complications. Thirty-eight of sixty-eight eyes received 5-FU and 30 received MMC. Mean postoperative follow-up was 7.5 and 6.5 years in the 5-FU and MMC groups, respectively (P=0.17). A higher proportion of eyes in the MMC group achieved "qualified" (with or without medical therapy) success with varying IOP targets relative to the 5-FU group, but the differences were not statistically significant. "Complete" (without medical therapy) postoperative success was greater in the MMC group with a significantly higher proportion achieving an IOP <21 mm Hg (P=0.02). MMC use was also associated with a lower likelihood of receiving IOP-lowering medications postoperatively (P=0.01). Baseline demographic characteristics, preoperative and postoperative IOP, visual acuity, and complications did not differ significantly between the 2 groups. Intraoperative MMC use is associated with a lower likelihood of requiring postoperative medications and a greater likelihood of achieving IOP lowering without medications relative to the use of 5-FU in a Black West African population. | 18,854,737 |
The Anglo-Scandinavian Cardiac Outcomes Trial: blood pressure-lowering limb: effects in patients with type II diabetes. | To compare the effects of two antihypertensive treatment strategies for the prevention of coronary heart disease and other cardiovascular events in the large subpopulation (n=5137) with diabetes mellitus in the blood pressure-lowering arm of the Anglo-Scandinavian Cardiac Outcomes Trial. Patients had either untreated hypertension or treated hypertension. For those with type II diabetes mellitus, inclusion criteria required at least two additional risk factors. Patients were randomized to amlodipine with addition of perindopril as required (amlodipine-based) or atenolol with addition of thiazide as required (atenolol-based). Therapy was titrated to achieve a target blood pressure of less than 130/80 mmHg. The trial was terminated early due to significant benefits on mortality and stroke associated with the amlodipine-based regimen. In patients with diabetes mellitus, the amlodipine-based treatment reduced the incidence of the composite endpoint--total cardiovascular events and procedures--compared with the atenolol-based regimen (hazard ratio 0.86, confidence interval 0.76-0.98, P=0.026). Fatal and nonfatal strokes were reduced by 25% (P=0.017), peripheral arterial disease by 48% (P=0.004) and noncoronary revascularization procedures by 57% (P<0.001). For the other endpoints included in the composite, the endpoint differences were less clear including coronary heart disease deaths and nonfatal myocardial infarctions (the primary endpoint), which were reduced nonsignificantly by 8% (hazard ratio 0.92, confidence interval 0.74-1.15). In the large diabetic subgroup in the blood pressure-lowering arm of the Anglo-Scandinavian Cardiac Outcomes Trial, the benefits of amlodipine-based treatment, compared with atenolol-based treatment, on the incidence of total cardiovascular events and procedures was significant (14% reduction) and similar to that observed in the total trial population (16% reduction). | 18,854,748 |
Anthropometric and dietary determinants of blood pressure in over 7000 Mediterranean women: the European Prospective Investigation into Cancer and Nutrition-Florence cohort. | Anthropometric characteristics and dietary habits are widely recognized to influence blood pressure. We evaluated their role in a large series of Mediterranean adult women. In Florence, in the European Prospective Investigation into Cancer and Nutrition, we recruited 10 083 women, aged 35-64 years. Detailed information on diet, lifestyle, physical activity, and medical history were collected. Anthropometric indices and systolic and diastolic blood pressures were measured at recruitment using standardized procedures. Overall, after excluding those women who reported a clinical diagnosis of hypertension and/or an antihypertensive treatment and those without measurements, 7601 women were available for analyses with an average systolic and diastolic blood pressure value of 123.2+/-16.0 and 78.7+/-9.4 mmHg, respectively. Multivariate regression models showed that body mass index (P<0.0001) and waist circumference (>or=88 cm, P<0.0001), as well as processed meat, potatoes, and wine consumption, were directly associated with both systolic and diastolic values. In contrast, a high consumption of selected foods resulted inversely associated with systolic (total vegetables, yoghurt, and eggs), diastolic (olive oil) or both systolic and diastolic values (leafy vegetables, milk, coffee). Analyses performed on nutrients showed a positive association with alcohol and sodium intake, and an inverse one with potassium and micronutrients derived from fruits and vegetables. In this large series of women from Tuscany, Central Italy, we confirm the independent influence of anthropometric characteristics on blood pressure. The role of specific foods and nutrients in modulating blood pressure also emerged, suggesting a central role for lifestyle modifications in blood pressure control. | 18,854,749 |
Interindividual variation in serum sodium and longitudinal blood pressure tracking in the Framingham Heart Study. | Recent cross-sectional studies have suggested that higher serum sodium levels may be a marker of elevated blood pressure. It is unclear whether serum sodium levels are related to the risk of developing hypertension in the community. We investigated the association of serum sodium with longitudinal blood pressure tracking and incidence of hypertension in 2172 nonhypertensive Framingham Offspring Study participants (mean age 42 years, 54% women). We defined an increase in blood pressure as an increment of at least one category (as defined by the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure), and incident hypertension as a systolic blood pressure of at least 140 or a diastolic blood pressure of at least 90 mmHg, or use of antihypertensive medications. Serum sodium was analyzed as a continuous variable, and as categories. Cross-sectionally, serum sodium was not associated with systolic or diastolic blood pressure (P exceeded 0.10). On follow-up (mean 4.4 years), 805 participants (37%, 418 women) progressed by at least one blood pressure category, and 318 (15%, 155 women) developed new-onset hypertension. In multivariable logistic regression analyses (adjusting for age, sex, baseline blood pressure, diabetes, BMI, weight gain and smoking), serum sodium was not associated with blood pressure progression (odds ratio per SD increment 0.93, 95% confidence interval 0.85-1.03), or with hypertension incidence (odds ratio per SD increment 0.94, 95% confidence interval 0.82-1.08). In our large community-based sample, serum sodium was not associated with blood pressure cross-sectionally, or with blood pressure tracking or hypertension incidence longitudinally. | 18,854,750 |
Nonalcoholic fatty liver disease, adiponectin and insulin resistance in dipper and nondipper essential hypertensive patients. | The pathogenesis of nonalcoholic fatty liver disease (NAFLD) is multifactorial, and the presence of insulin resistance is recognized as the pathophysiological hallmark of this condition. Arterial hypertension is referred as an insulin-resistant state, and insulin resistance may substantially contribute to the cardiovascular risk in this disorder. We examined the inter-relationship between insulin sensitivity, adiponectin levels, and NAFLD in hypertensive patients with different circadian blood pressure profiles. Eighty never-treated patients with essential hypertension were selected for having a nocturnal decrement of blood pressure that was at least 10% (dippers, n=47) or less than 10% (nondippers, n=33) of daytime values. No patient had diabetes mellitus, obesity, hyperlipidemia, or other risk factors for hepatic disease. The two groups were similar as to sex, age, and BMI. Abdominal fat distribution and NAFLD were assessed by ultrasonography. Hepatic steatosis was detected in 57.5% of all patients. Nondippers showed a higher prevalence of NAFLD than dippers (81.8 vs. 40.4%, P<0.005). Insulin and the homeostasis model of assessment index were higher (P<0.001) and adiponectin was lower (P<0.001) in nondippers than in dippers, whereas no difference was found in regional fat, liver enzymes, and other metabolic parameters. At multivariate analysis, factors independently associated with nondipping were insulin (P<0.05) and adiponectin (P<0.01) with the homeostasis model of assessment index being of borderline significance. In the absence of major risk factors for the development of NAFLD, a high prevalence of liver steatosis was associated with insulin resistance and low adiponectin levels in essential hypertensive patients with a nondipping profile. | 18,854,760 |
Switch of immunosuppression from cyclosporine A to everolimus: impact on pulse wave velocity in stable de-novo renal allograft recipients. | Cardiovascular mortality is extraordinarily high in renal allograft recipients and accounts for almost half of all allograft losses. Whereas the immunosuppression with calcineurin inhibitors is associated with an increased cardiovascular risk, beneficial effects of mammalian target of rapamycin inhibitors on the vascular system are suspected. In a randomized clinical trial, we evaluated the impact on pulse wave velocity (PWV) of a switch from cyclosporine A (CsA) to everolimus (EVR), 6 months after transplantation, in 27 stable de-novo renal allograft recipients. PWV was assessed before and after randomization to the different immunosuppressive protocols at 6 and 15 months post-transplantation, respectively. Seventeen out of 27 patients included in the analysis were switched to EVR; 10 out of 27 were kept on CsA. The switch of immunosuppressive therapy from CsA to EVR resulted in stable PWV (9.50+/-1.92 vs. 9.13+/-1.62 m/s, DeltaPWV= -0.37+/-1.14 m/s, P=0.16), whereas a significant increase of PWV (9.93+/-1.94 vs. 10.8+/-2.24 m/s, DeltaPWV=0.89+/-1.47 m/s, P=0.03) was observed in patients on continued CsA therapy. In renal allograft recipients, the prolonged treatment with CsA was associated with a significant increase of PWV whereas no further deterioration of large vessel compliance was observed in patients that were switched to EVR 6 months post transplantation. The cardiovascular risk profile in stable de-novo renal allograft recipients might therefore be positively impacted by an early switch of the primary immunosuppressive therapy from CsA to EVR. | 18,854,763 |
Oxidative stress after uninephrectomy alters heart morphology in the apolipoprotein E -/- mouse. | Even minor reduction in glomerular filtration rate accelerates atherogenesis and increases cardiovascular risk. The current study on the apolipoprotein E -/- mouse was designed to investigate whether nephron reduction by uninephrectomy causes cardiac remodeling and whether this is prevented by antioxidative treatment. We randomized apolipoprotein E -/- mice to undergo uninephrectomy or sham operation and subsequent treatment with either Tempol, Ebselen, Trandolapril, or a combination of Tempol and Trandolapril. After 12 weeks, the experiment was terminated by perfusion fixation under anesthesia. The myocardium was analyzed by morphometry. Additionally, the expression of endothelial nitric oxide synthase, transforming growth factor-beta1, vascular endothelial growth factor, flt-1, collagen I and presence of nitrotyrosine were assessed using immunohistochemistry or western blotting. Untreated uninephrectomized animals had lower capillary length density and higher volume fraction of interstitial tissue in the myocardium and bigger plaques in aorta compared with those who underwent sham operation. These changes did not develop in uninephrectomized animals treated with Tempol, Ebselen, Trandolapril, or Tempol + Trandolapril. In untreated uninephrectomized mice, the presence of nitrotyrosine and the expression of transforming growth factor-beta1, vascular endothelial growth factor, and collagen I were more marked. This was ameliorated by Tempol, Ebselen, Trandolapril, and Tempol + Trandolapril. We conclude that in the apolipoprotein E -/- mouse, even minor reduction in renal function, for example, by uninephrectomy, causes remodeling of the heart. This was ameliorated to a similar extent by antioxidants and angiotensin-converting enzyme inhibition. | 18,854,764 |
Percutaneous versus surgical bedside tracheostomy in the intensive care unit: a cohort study. | To compare the outcomes, as well as the short and long term complications, of percutaneous dilational tracheostomy (PDT) and surgical tracheostomy (ST) at the bedside. From 2003 to 2005, 367 consecutive patients underwent percutaneous tracheostomy in two general ICUs of a community hospital. Short and long term complications, procedural time, duration on mechanical ventilation, length of stay in the ICU and in the hospital, and mortality rates were compared to a historical cohort of 161 patients treated with surgical tracheostomy. Both groups were comparable in demographic characteristics and severity scores. As a whole, 528 mechanically ventilated patients underwent tracheostomy at the bedside. 161 patients received ST and 367 PDT by the single dilator technique. Only minor complications were observed in both groups of patients. PDT was performed more rapidly than ST (5.4+/-5.2 vs 19+/-10 min). STs were performed significantly later than PDT (12.4+/-6 days vs 8.7+/-5.8 days, P<0.05). The overall ICU stay and mean duration of mechanical ventilation were lower in the PDT than in the ST group (18.4+/-13.9 vs 23.3+/-15.8 days, P< 0.05 and 14.2+/-8.1 vs 20.1+/-10.4, P<0.05, respectively). There were no statistically significance differences in ICU and hospital outcome between the two techniques. Compared with ST, the main advantage of PDT is that it is more rapid and allows the tracheostomy to be performed earlier in the course of ventilatory failure. Early tracheostomy is associated with a shorter duration of mechanical ventilation and a reduced ICU length of stay. | 18,854,794 |
Dilatative percutaneous tracheostomy during double antiplatelet therapy: two consecutive cases. | This article reports two cases of dilatative percutaneous tracheostomy performed on patients treated with double antiplatelet therapy. Both patients had cardiac arrest following myocardial infarction. After primary angioplasty with stent placement, a double antiplatelet therapy was started. Due to poor neurological outcome, dilatative percutaneous tracheostomy was performed on both patients. Antiplatelet therapy was not discontinued because of the unacceptable risk of stent thrombosis. No immediate or late hemorrhagic complications occurred. In our experience, dilatative percutaneous tracheostomy during double antiplatelet therapy can be safely performed in selected patients without other risk factors. | 18,854,797 |
[Anticoagulant prophylaxis in women affected by thrombophilia and previous obstetric complications]. | Pregnancy is a condition of excessive clotting due to a decrease of some coagulation factors and a reduction of anticoagulant proteins, such as protein S. It is known that the causes of congenital or acquired thrombophilia may be associated with an increased risk of venous thromboembolism during pregnancy and/or obstetric complications, such early or late fetal loss, intrauterine fetal deaths, pre-eclampsia, fetal growth restriction. During pregnancy the use of a prophylaxis with antithrombotic drugs is considered at present a promising opportunity to significantly reduce the prevalence of thromboembolic complications, improving maternal and fetal outcomes. This article is a review to most recent evidence of pregnant anticoagulant prophylaxis in women with previous thromboembolic events. | 18,854,809 |
C-Fos expression is a molecular predictor of progression and survival in epithelial ovarian carcinoma. | Members of the Fos protein family dimerise with Jun proteins to form the AP-1 transcription factor complex. They have a central function in proliferation and differentiation of normal tissue as well as in oncogenic transformation and tumour progression. We analysed the expression of c-Fos, FosB, Fra-1 and Fra-2 to investigate the function of Fos transcription factors in ovarian cancer. A total of 101 patients were included in the study. Expression of Fos proteins was determined by western blot analysis, quantified by densitometry and verified by immunohistochemistry. Reduced c-Fos expression was independently associated with unfavourable progression-free survival (20.6, 31.6 and 51.2 months for patients with low, moderate and high c-Fos expression; P=0.003) as well as overall survival (23.8, 46.0 and 55.5 months for low, moderate and high c-Fos levels; P=0.003). No correlations were observed for FosB, Fra-1 and Fra-2. We conclude that loss of c-Fos expression is associated with tumour progression in ovarian carcinoma and that c-Fos may be a prognostic factor. These results are in contrast to the classic concept of c-Fos as an oncogene, but are supported by the recently discovered tumour-suppressing and proapoptotic function of c-Fos in various cancer types. | 18,854,825 |
Inhibition of HIF-1alpha by the anticancer drug TAS106 enhances X-ray-induced apoptosis in vitro and in vivo. | In a previous study, we showed that a novel anticancer drug, 1-(3-C-ethynyl-beta-D-ribo-pentofuranosyl)cytosine (TAS106, ECyd) increased the antitumour efficacy of X-irradiation. However, its effects on hypoxic cells in tumours remain unclarified. Here, we show that TAS106 enhances the induction of apoptosis in X-irradiated human gastric adenocarcinoma MKN45 and MKN28 cells under hypoxia in vitro. At the same time, the accumulation of HIF-1alpha observed under hypoxia was shown to be decreased to the level of normoxia in the presence of 0.1 microM TAS106. To study the function of HIF-1alpha protein in apoptosis of hypoxic cells, we employed an HIF-1alpha reductive approach using its specific antisense oligodeoxynucleotide. The reduction of HIF-1alpha gene expression dramatically enhanced X-ray-induced apoptosis in hypoxic cells. In in vivo experiments in which MKN45 cells were transplanted into severe combined immunodeficient (SCID) mice, TAS106 (0.5 mg kg(-1)) suppressed HIF-1alpha expression and subsequently reduced the area of the hypoxic region in the tumour and enhanced the induction of apoptosis in the hypoxic region when combined with 2 Gy of X-irradiation. These results suggest the possibility that TAS106 acts as a potent radiosensitiser through the inhibition of HIF-1alpha expression and can be a useful agent against radiotherapy-resistant hypoxic cells in solid tumours. | 18,854,835 |
The prognostic impact of NF-kappaB p105, vimentin, E-cadherin and Par6 expression in epithelial and stromal compartment in non-small-cell lung cancer. | Vimentin, nuclear factor-kappaB (NF-kappaB) p105, fascin, E-cadherin, TGF-beta, Par6 and atypical PKC are molecular markers that play an important role in cell differentiation. Herein, we investigate their prognostic impact in primary non-small-cell carcinoma (NSCLC). Tumour tissue samples from 335 resected patients with stage I-IIIA were used. Tissue microarrays were constructed from duplicate cores of both neoplastic cells and stromal cells and were immunohistochemically evaluated. In univariate analyses, high tumour epithelial cell expressions of NF-kappaB p105 (P=0.02) and E-cadherin (P=0.03) were positive prognostic indicators for disease-specific survival (DSS), whereas high tumour epithelial cell expression of vimentin (P=0.001) was a negative prognostic indicator. High expression of NF-kappaB p105 (P=0.001) and Par6 (P=0.0001) in the stromal compartment correlated with a good prognosis. In multivariate analyses, the tumour epithelial cell expression of NF-kappaB p105 (P=0.0001) and vimentin (P=0.005) and the stromal cell expression of NF-kappaB p105 (P=0.007) and Par6 (P=0.0001) were independent prognostic factors for DSS. High expression of NF-kappaB p105 and low expression of vimentin in tumour epithelial cells are independent predictors of better survival in primary NSCLC. In stromal cells, high expressions of NF-kappaB p105 and Par6 are both favourable independent prognostic indicators. | 18,854,838 |
The first solid composed of [As4V16O42(H2O)] clusters. | A new polyoxovanadate [Zn2(dien)3][[Zn(dien)]2As4V16O42(H2O)] x 3H2O (1, dien = diethylenetriamine) has been hydrothermally synthesized and structurally characterized by EA, IR, TGA, magnetic measurement and single crystal X-ray diffraction. X-Ray diffraction analyses reveal that 1 exhibits the first [As4V16O42(H2O)]-containing polyoxometalate. In 1, the adjacent [As4V16O42(H2O)] clusters are linked to each other through dual mono-nuclear zinc complexes {Zn(dien)} to form one-dimensional anionic chains with isolated dinuclear zinc complexes [Zn2(dien)3] occupying the interchain regions as charge compensation. The study of the magnetic susceptibility demonstrates the presence of antiferromagnetic interaction between VIV cations in 1. | 18,854,895 |
The structure of Fe(III) ions in strongly alkaline aqueous solutions from EXAFS and Mössbauer spectroscopy. | To establish the structure of ferric ions in strongly alkaline (pH > 13) environments, aqueous NaOH solutions supersaturated with respect to Fe(III) and the solid ferric-hydroxo complex salts precipitating from them have been characterized with a variety of experimental techniques. From UV measurements, in solutions of pH > 13, only one kind of Fe(III)-hydroxo complex species was found to be present. The micro crystals obtained from such solutions were proven to be a new, so far unidentified solid phase. Mössbauer spectra of the quick-frozen solution and that of the complex salt indicated a highly symmetrical ferric environment in both systems From the EXAFS and XANES spectra, the environment of the ferric ion in these solutions (both native and quick-frozen) and in the complex salt was found to be different. In the complex salt, the bond lengths are consistent with an octahedral coordination around the ferric centres. In solution, the coordination geometry of Fe(III) is most probably tetrahedral. Our results demonstrate that in strongly alkaline aqueous solutions, ferric ions behave very similarly to other structurally related tervalent ions, like Al(III) or Ga(III). | 18,854,898 |
Syntheses and structures of half-sandwich iridium(III) and rhodium(III) complexes with organochalcogen (S, Se) ligands bearing N-methylimidazole and their use as catalysts for norbornene polymerization. | The organochalcogen ligands derived from 3-methyl-imidazole-2-thione/selone groups, Mbit, Mbis, Ebit and Ebis [Mbit = 1,1'-methylenebis(3-methyl-imidazole-2-thione); Mbis = 1,1'-methylenebis(3-methyl-imidazole-2-selone), Ebit = 1,1'-(1,2-ethanediyl)bis(3-methyl-imidazole-2-thione), Ebis = 1,1'-(1,2-ethanediyl)bis(3-methyl-imidazole-2-selone)] have been synthesized and characterized. Reactions of [Cp*Ir(micro-Cl)Cl]2 and [Cp*Rh(micro-Cl)Cl]2 (Cp* = eta5-pentamethylcyclopentadienyl) with Mbit, Mbis, Ebit and Ebis result in the formation of the complexes [Cp*Ir(Mbit)Cl]Cl 1a x Cl), [Cp*Ir(Mbis)Cl]Cl (3a x Cl), [Cp*Ir(Ebit)Cl]Cl (1b x Cl), [Cp*Ir(Ebis)Cl]Cl (2a x Cl), [Cp*Rh(Mbit)Cl]Cl (2b x Cl), Cp*Rh(Mbis)Cl][Cp*RhCl(3)] (3b x[Cp*RhCl(3)]), [Cp*Rh(Ebit)Cl]Cl (4a x Cl) and [Cp*Rh(Ebis)Cl]Cl (4b x Cl), respectively. All compounds have been characterized by elemental analysis, NMR and IR spectra. The molecular structures of 1b, 2b, 3a, 3b and 4a have been determined by X-ray crystallography. After activation with methylaluminoxane (MAO), the iridium complexes exhibit moderate activities for the vinyl polymerization of norbornene. | 18,854,899 |
Composition, distribution and characterization of polybrominated diphenyl ethers (PBDEs) in the soil in Taiyuan, China. | A total of 21 surface soil samples covering the whole territory of Taiyuan city were collected for analysis the 39 polybrominated diphenyl ethers (PBDEs). The total PBDEs concentration ranged from 0.016 to 211.416 ng g(-1) in urban soils and 5.961 to 144.162 ng g(-1) in industrial plant soils. PBDE homologues analysis and principal component analysis (PCA) revealed that the major source of PBDEs in Taiyuan might be potentially associated with the prevalent use of deca-BDE as a flame retardant. Furthermore, increasing PBDEs contamination was observed in north Taiyuan because of the degree of urbanization and the distribution of industrial plants. | 18,854,905 |
Early and midterm outcomes of open stent-graft treatment for distal aortic arch aneurysm. | The aim of this study was to investigate early and late outcomes for open stent-graft treatment, which was introduced as a less-invasive technique for thoracic aortic aneurysm of the distal arch, and to clarify the validity of and indications for this treatment. We retrospectively investigated 38 patients with thoracic aortic aneurysm of the distal arch who underwent open stent-graft placement at our hospital between June 2000 and September 2006. Five patients died in hospital (hospital mortality 13.2%). Age at the time of surgery and onset of postoperative paraplegia were identified as risk factors. Four patients (10.5%) had postoperative paraplegia, but no significant risk factors were seen. The size of the aneurysm was clearly reduced in 18 of the 25 patients (75.8%), in whom computed tomography was performed after discharge, and late outcomes were good. Mural thrombus thickness on the stent landing zone of <4 mm was a predictor for aneurysm shrinkage. Seven patients died during the late period, and the 5-year survival rate among hospital survivors was 80.1%. Early outcomes for open stent-graft are not necessarily good, and late survival is also not excellent. Open stent-graft thus cannot be regarded as an ideal technique for all patients with distal aortic arch aneurysm. However, after aneurysm shrinkage was confirmed during the early period, late outcomes were good. Absence of thick mural thrombus on the stent landing zone may represent a good indication for open stentgraft surgery. | 18,854,925 |
Mitral valve replacement for extensive calcification: half and half technique. | A 50-year-old woman who had been undergoing hemodialysis for 18 years underwent mitral valve replacement because of mitral valve stenosis. Her mitral valve leaflet and annulus were highly calcified, and it was impossible to remove the posterior leaflet from the ventricular wall. At the time of surgery, noneverted horizontal mattress sutures were placed from the left ventricle to the left atrium on the anterior half of the mitral annulus and everted horizontal mattress sutures on the left atrial wall close to the calcified posterior annulus. A 25-mm St. Jude valve was seated successfully at a supra-annular position. The St. Jude valve is suitable for this technique because its leaflets protrude less into the left ventricle. | 18,854,933 |
Adipocyte differentiation of bone marrow-derived mesenchymal stem cells: cross talk with the osteoblastogenic program. | Bone marrow mesenchymal stem cells (MSCs) are multipotent cells, which among other cell lineages, give rise to adipocytes and osteoblasts. Within the bone marrow, the differentiation of MSCs into adipocytes or osteoblasts is competitively balanced; mechanisms that promote one cell fate actively suppress mechanisms that induce the alternative lineage. This occurs through the cross talk between complex signaling pathways including those derived from bone morphogenic proteins (BMPs), winglesstype MMTV integration site (Wnt) proteins, hedgehogs, delta/jagged proteins, fibroblastic growth factors (FGF), insulin, insulin-like growth factors (IGF), and transcriptional regulators of adipocyte and osteoblast differentiation including peroxisome proliferator-activated receptor-gamma (PPAR gamma) and runt-related transcription factor 2 (Runx2). Here, we discuss the molecular regulation of bone marrow adipogenesis with emphasis on signals that interact with osteoblastogenic pathways and highlight the possible therapeutic implications of these interactions. | 18,854,943 |
Bile acid alone, or in combination with acid, induces CDX2 expression through activation of the epidermal growth factor receptor (EGFR). | Bile acids and acid are implicated in the development of Barrett's esophagus. Evidence suggests that Barrett's esophagus intestinal metaplasia may occur via induction of caudal homeobox gene 2 (CDX2). We hypothesized that induction of CDX2 by bile acids may be due to ligand-dependent transactivation of epidermal growth factor receptor (EGFR). Human mucosal epithelial cells (SEG-1) were treated for 0 to 24 h with up to 300 microM deoxycholic acid (DCA) at pH 7 or 5 with or without (w/wo) antibodies against EGFR ligand-binding site (Mab528, 3-5 mug/ml). Treatment with 100 ng/ml EGF served as control. CDX2 mRNA expression was determined by real-time polymerase chain reaction. EGFR activation was analyzed by Westerns of phosphorylated EGFR tyrosines. Acid (pH 5) increased the induction of CDX2 mRNA expression caused by DCA. CDX2 mRNA induction was markedly reduced by EGFR blockade with Mab528. Each treatment (pH 5, DCA or pH 5 plus DCA) activated the EGFR on all tyrosines tested but in different time courses. Phosphorylation by DCA was inhibited by Mab528. Activation of EGFR by DCA at pH 5 resulted in EGFR degradation, while that by DCA alone did not. Thus, CDX2 induction by DCA w/wo acid occurs through ligand-dependent transactivation of the EGFR. The variations in EGFR degradation pattern with DCA or DCA at pH 5 indicate differential transactivation pathways. The molecular pathogenesis of Barrett's esophagus may occur via bile-stimulated cell signaling through the EGFR. | 18,854,960 |
[Single base polymorphisms and erectile dysfunction]. | The risk for erectile dysfunction is closely linked to cardiovascular morbidities such as coronary heart disease, arterial hypertension, hypercholesterolemia, and diabetes. Molecular analysis revealed an association between the genotypes in single base polymorphisms and the risk for these cardiovascular morbidities. In this review the current knowledge of association studies of single nucleotide polymorphisms and erectile dysfunction and the response to the PDE-5 inhibitor sildenafil is described. | 18,854,967 |
Specialist team retrieval of head injured patients: fact, fiction, or formula? | This feasibility study aimed to determine the maximum theoretical distance the Edinburgh Paediatric Retrieval Team (EPRT) could travel to retrieve head injured children without additional delay in reaching definitive care. A prospective audit was conducted over 2 years to determine the current practice for paediatric head injury transfers (stabilisation, referral, and transfer time) undertaken by primary hospital staff, and the performance (mobilisation and travel time) of the EPRT. A novel formula was devised and used to determine the theoretical maximum radius within which the EPRT could reach a referring hospital during their stabilisation of head injured patients. During the study period, 27 head injured patients were transferred to our unit by road and the EPRT conducted 194 road retrievals. The median stabilisation time for the head injured patients was 3.6 h. Median time to refer these patients to neurosurgical services was 1 h after presenting to primary hospitals. Median mobilisation time for EPRT was 1 h. Using our novel formula, 67 miles was the theoretical maximum radius within which the EPRT could reach a referring hospital during their stabilisation of head injured patients. Specialist team retrieval of paediatric head injury is a possibility, but not without significant organisational changes such as availability of second teams, early referral of patients and utilisation of the mobilisation time as a cancellation window. Our novel formula offers other teams a starting point to assess their own performance and to develop services. | 18,854,974 |
Effects of sibutramine and rimonabant in rats trained to discriminate between 22- and 2-h food deprivation. | The objective of the study was to evaluate whether sibutramine and rimonabant, drugs that decrease food intake in human and non-human animals, affect the discriminative stimulus effects associated with acute food deprivation ("hunger"). Rats were trained to discriminate between 22- and 2-h food deprivation in a two-lever choice procedure. After rats acquired the discrimination, subjects were food-restricted for 22 h and administered with sibutramine (0.32-10 mg/kg, p.o.) or rimonabant (0.32-10 mg/kg, s.c.) before a generalization test session. Sibutramine (3.2 mg/kg) produced significant decreases in 22-h deprivation-appropriate responding, response rates (resulting in lever pressing rates similar to those following 2-h food deprivation), and food intake measured 1 h after the generalization test. A larger sibutramine dose eliminated responding and significantly reduced food intake. Rimonabant did not alter the discriminative stimulus effects of 22-h food deprivation, but rimonabant did significantly reduce both response rates and food intake. Sibutramine appears to decrease food intake by reducing hunger sensations associated with food deprivation. In contrast, rimonabant does not alter the discrimination of acute food deprivation. The use of food-deprivation discrimination techniques may be useful in identifying the role of specific neuroactive compounds in eating stimulated by a sense of hunger and may aid in medication development for more effective treatments for obesity and other eating-related conditions. | 18,854,986 |
[The spectrum of microbiological agents causing pulmonary MALT-type lymphomas. A 16S rRNA-based analysis of microbial diversity]. | For several anatomical localisations of extranodal marginal zone B-cell lymphoma of MALT type (eMZBCL), an association with chronic inflammation caused by microbiological agents (e.g. Helicobacter pylori in the stomach) has been described. In the lung, a link between lymphomagenesis and a defined causative organism is still missing. A comprehensive diversity survey using 16S-rDNA library construction followed by restriction fragment length polymorphism (RFLP) analysis, sequencing, and phylogenetic tree construction was employed for nine cases each of BALT lymphoma and control lung tissues (normal foetal lung, pneumonitis, carcinoid). This highly sensitive method, hereafter termed SHARP screening allowed for identification of the entire bacterial population in the tissue in a cultivation-independent manner. It was noteworthy that in eight of the nine cases of BALT lymphoma, bacteria of the Alcaligenaceae family (Alcaligenes, Achromobacter, AKIW733), were detected, whereas none of the control cases showed the presence of these clades. 16S-rDNA library construction in combination with RFLP screening and phylogenetic analyses, hereafter described as SHARP screening, is a cultivation-independent tool for analysing the microbial environment in chronic inflammation processes giving rise to extranodal marginal zone B-cell lymphomas of MALT-type. Betaproteobacteria of the Alcaligenaceae family may be affiliated with and possibly involved in the lymphomagenesis of BALT lymphomas. | 18,854,998 |
Analysis of CYP7B1 in non-consanguineous cases of hereditary spastic paraplegia. | Hereditary spastic paraplegia (HSP) is a neurodegenerative condition defined clinically by lower limb spasticity and weakness. Homozygous mutations in CYP7B1 have been identified in several consanguineous families that represented HSP type 5 (SPG5), one of the many genetic forms of the disease. We used direct sequencing and multiplex ligation-dependent probe amplification to screen for CYP7B1 alterations in apparently sporadic HSP patients (n = 12) as well as index patients from non-consanguineous families with recessive (n = 8) and dominant (n = 8) transmission of HSP. One sporadic patient showing HSP as well as optic atrophy carried a homozygous nonsense mutation. Compound heterozygosity was observed in a recessive family with a clinically pure phenotype. A heterozygous missense change segregated in a small dominant family. We also found a significant association of a known coding polymorphism with cerebellar signs complicating a primary HSP phenotype. Our findings suggest CYP7B1 alterations to represent a rather frequent cause of HSP that should be considered in patients with various clinical presentations. | 18,855,023 |
Toxoplasma gondii antibody profile in HIV-infected pregnant women and the risk of congenital toxoplasmosis. | The purpose of this study was to investigate the antibodies to Toxoplasma gondii in human immunodeficiency virus (HIV)-infected pregnant women and to determine the association between serological profile and the risk of congenital toxoplasmosis. The study, conducted in a public maternity ward from May 2002 to April 2005, included all HIV-infected women who delivered live infants during the 36 months, and, as a control group, all HIV-negative women that delivered live infants in the first 12 months of the study. Antibodies to T. gondii were detected in 1,624 of 2,421 HIV-negative women (67%; 95% confidence interval [CI] 65-69%) and in 121 of 168 HIV-infected patients (72%; 95% CI 65-79%). A total of 547 HIV-negative and 103 HIV-infected patients were tested at delivery and had positive T. gondii-specific IgG. In HIV-negative women, the median of the specific IgG concentration was 79 (interquartile range 38-160), and in HIV-infected patients, it was 283 (interquartile range 94-704) (P < 0.001). In the group of co-infected women, the only infant with congenital toxoplasmosis was born to a mother with acute toxoplasmosis infection acquired during pregnancy who did not have a high specific IgG concentration or a positive result for specific IgM. We concluded that high T. gondii-specific IgG values were much more frequent among HIV-infected pregnant women, but it did not translate into an increased risk of maternal-fetal transmission of toxoplasmosis. | 18,855,029 |
Feasibility of measuring trabecular bone structure of the proximal femur using 64-slice multidetector computed tomography in a clinical setting. | We studied the feasibility of cancellous bone structure assessment of the proximal femur using multidetector computed tomography (MDCT) in an simulated in vivo experimental model. The proximal femur of 15 intact human cadavers was examined using 64-row MDCT using a thin-section protocol with an in-plane spatial resolution of 273 mum. High-resolution peripheral quantitative computed tomography (HR-pQCT) of the isolated specimens with a voxel size of 82 mum served as a standard of reference. Trabecular bone structure and optimized textural parameters were calculated in MDCT images and compared to measures obtained by HR-pQCT. Significant correlations between MDCT- and HR-pQCT-derived values for bone fraction (r = 0.87), trabecular separation (r = 0.66), and number (r = 0.53) were found. Parameters derived from textural analysis performed better in predicting trabecular separation (up to r = 0.86) and number (up to r = 0.83). Trabecular thickness could not be quantified correctly using MDCT, most likely due to its limited resolution. Individual parameters for assessement of trabecular microarchitecture can be measured using MDCT-derived imaging studies and a simulated in vivo setup. Thus, in vivo assessment of bone architecture in addition to BMD may be feasible in clinical practice. | 18,855,036 |
Is a circular polypropylene mesh appropriate for application at the esophageal hiatus? Results from an experimental study in a porcine model. | Mesh reinforcement in hiatal hernia surgery is debated. Randomized controlled trials have shown that recurrences may be reduced, but there is also the fear of mesh-related complications. Experimental studies on the characteristics of specific mesh types with regard to the risk of such complications are rare. The current study aimed to investigate the properties of a circular heavy-weight polypropylene mesh in terms of stenosis, migration, erosions, and adhesions in a porcine model. A 55 x 55-mm heavy-weight polypropylene mesh with a 16.5-mm eccentric hole for the esophagus corresponding to a calculated mesh area of 2811 mm(2) and a hole area of 214 mm(2) were implanted in nine German Landrace pigs. Six weeks later, the meshes were explanted and investigated for size, shrinkage, migration and adhesions. The total mesh area shrank to a mean of 2,040 +/- 178 mm(2) (p < 0.001), and the hole for the esophagus showed a trend toward an increase to 239 +/- 38 mm(2) (p = 0.108). In not a single location did the mesh overhang the hiatal margin. The mean distance of retraction from the hiatal margin was 4.3 +/- 2.8 mm. Therefore, no stenoses, migrations, or erosions occurred. A circular heavy-weight polypropylene mesh seems to be appropriate for the application at the esophageal hiatus in terms of safety and stability. This means that it is characterized by a position-stable centered fixation around the esophagus without a tendency toward stenosis, migration, or erosion. | 18,855,052 |
Ergonomics, user comfort, and performance in standard and robot-assisted laparoscopic surgery. | Robot-assisted surgical systems have been introduced to improve the outcome of minimally invasive surgery. These systems also have the potential to improve ergonomics for the surgeon during endoscopic surgery. This study aimed to compare the user's mental and physical comfort in performing standard laparoscopic and robot-assisted techniques. Surgical performance also was analyzed. In this study, 16 surgically inexperienced participants performed three tasks using both a robotic system and standard laparoscopic instrumentation. Distress was measured using questionnaires and an ambulatory monitoring system. Surgical performance was analyzed with time-action analysis. The physiologic parameters (p = 0.000), the questionnaires (p = 0.000), and the time-action analysis (p = 0.001) favored the robot-assisted group in terms of lower stress load and an increase in work efficiency. In this experimental setup, the use of a robot-assisted surgical system was of value in both cognitive and physical stress reduction. Robotic assistance also demonstrated improvement in performance. | 18,855,053 |
Natural orifice translumenal endoscopic drainage for pancreatic abscesses. | Few series describe endoscopic drainage of pancreatic abscesses. Abscesses are complications of pancreatitis, presenting with sepsis, peritonitis, or both. This report describes the feasibility and efficacy of natural orifice translumenal endoscopic surgery for pancreatic abscesses. This study reviewed 35 consecutively treated patients for the period 1994-2007. The approaches alone or in combination were transmural (transgastric or transduodenal) and transpapillary. The criteria for abscesses were two or more of the following: fever, abdominal pain, elevated white blood count (WBC), and positive fluid cultures. The 35 patients (19 men and 16 women) had a mean age of 49 years. The abscesses had idiopathic (37%), gallstone (32%), alcohol (20%), and divisum (11%) etiologies. The presenting signs were abdominal pain (80%), positive cultures (69%), fever (57%), elevated WBC (51%), and nausea/vomiting (39%). The approaches for abscess drainage were as follows: transgastric (n = 15, 43%), transduodenal (n = 4, 11%), transgastric combined with transpapillary (n = 8, 23%), transduodenal combined with transpapillary (n = 1, 3%), and transpapillary alone (n = 7, 20%). A total of 28 patients (80%) achieved successful endoscopic pancreatic abscess drainage, whereas 7 (20%) required surgery. Of these seven patients, two (6%) required emergent laparotomy to control bleeding, and the remaining five (14%) were explored after failure to demonstrate clinical improvement from endoscopic drainage. Three patients required internal drainage, and two patients required distal pancreatectomy. The mean follow-up period was 15 months, and the complication rate was 6%. No one died from the procedure. Endoscopic surgery for pancreatic abscess is feasible and effective. It is an alternative to surgery that currently can be considered a primary treatment option for selected pancreatic abscesses. | 18,855,067 |
The FTO obesity gene. Genotyping and gene expression analysis in morbidly obese patients. | Obesity has emerged as one of the most serious public health concerns in the twenty-first century. the fat mass and obesity associated gene (FTO) has been found to contribute to the risk of obesity in humans. Our aims in this study were to investigate the association of rs9939609 single nucleotide polymorphism (SNP) of the FTO gene with different obesity-related parameters, to assess the FTO gene expression in subcutaneous and visceral adipose tissues from morbidly obese and its correlations with other adipocytokine gene expressions. The association between the rs9939609 FTO gene variant and obesity related parameters in 75 obese/morbidly obese adult patients and 180 subjects with body mass index (BMI) < 30 kg/m(2) (control group) was examined. Gene expression analyses: subcutaneous adipose tissue samples were obtained from 52 morbidly obese and five subjects with BMI < 30 kg/m(2). Visceral adipose tissue was also obtained from 35 morbidly obese patients. Weight, height, BMI, SBP, DBP, fasting glucose, lipid profile, proinsulin, insulin, leptin, and adiponectin (RIA) of patients were also obtained. Insulin resistance by HOMA(IR). rs9939609 of FTO genotyping using allele discrimination in real-time PCR. Genomic study of RNA extraction of adipose tissue and real-time PCR (RT-PCR) of adipocytokines and a housekeeping gene were quantified using TaqMan probes. Relative quantification was calculated using the DeltaDelta Ct formula. The minor-(A) allele frequency of rs9939609 FTO gene in the whole population was 0.39. A strong association between this A allele and obesity was found, even after age-sex adjustment (p = 0.013). We found higher levels of FTO mRNA in subcutaneous adipose tissue from morbidly obese than in the control group (p = 0.021). FTO gene expression was lower in visceral than in subcutaneous adipose depot. However, this finding did not reach the level of statistical significance. A negative correlation between subcutaneous FTO gene expression and serum triglyceride levels and a positive correlation with leptin, perilipin, and visfatin gene expressions was found. In the visceral adipose tissue, these positive correlations were statistically significant only for perilipin. Our results show: (1) A strong association between rs9939609 SNP of the FTO gene variant and obesity in Spanish morbidly obese adult patients; (2) positive correlations between FTO mRNA and leptin, perilipin, and visfatin gene expressions in subcutaneous adipose tissue; (3) FTO and perilipin gene expressions were positively correlated in visceral fat depot. Overall these results may suggest a role of FTO in the regulation of lipolysis as well as in total body fat rather in fat distribution patterns. | 18,855,084 |
Extremely small-magnitude accelerations enhance bone regeneration: a preliminary study. | High-frequency, low-magnitude accelerations can be anabolic and anticatabolic to bone. We tested the hypothesis that application of these mechanical signals can accelerate bone regeneration in scaffolded and nonscaffolded calvarial defects. The cranium of experimental rats (n = 8) in which the 5-mm bilateral defects either contained a collagen scaffold or were left empty received oscillatory accelerations (45 Hz, 0.4 g) for 20 minutes per day for 3 weeks. Compared with scaffolded defects in the untreated control group (n = 6), defects with a scaffold and subject to oscillatory accelerations had a 265% greater fractional bone defect area 4 weeks after the surgery. After 8 weeks of healing (1-week recovery, 3 weeks of stimulation, 4 weeks without stimulation), the area (181%), volume (137%), and thickness (53%) of the regenerating tissue in the scaffolded defect were greater in experimental than in control animals. In unscaffolded defects, mechanical stimulation induced an 84% greater bone volume and a 33% greater thickness in the defect. These data provide preliminary evidence that extremely low-level, high-frequency accelerations can enhance osseous regenerative processes, particularly in the presence of a supporting scaffold. | 18,855,088 |
State estimation in the cerebellum. | An exciting hypothesis about the cerebellum is that its role is one of state estimation--a process that combines efferent copies of motor commands with afferent sensory signals to produce a representation of the current status of the peripheral motor system. Sensory inputs alone cannot provide a perfect state signal because of inevitable delays in their afferent pathways. We have recently reported the effects of transcranial magnetic stimulation (TMS) over the ipsilateral cerebellum as healthy subjects made rapid reaching movements towards visually defined targets (Miall et al. in PLoS Biology 5:2733-2744, 2007). Errors in the initial direction and in the final finger position of this reach-to-target movement were consistent with the reaching movements being planned and initiated from an estimated hand position that was about 138 ms out of date. This interval is consistent with estimates of the delays in sensory motor pathways that would inform the central nervous system of the peripheral status. We now report new data using the same paradigm, testing the effects of varying the TMS stimulus train from one, two, or three pulses. We show that the errors in movement are relatively insensitive to the TMS pulse-train duration. The estimated time interval by which the hand position is mislocalized varied by only 12 ms as the TMS train duration increased by 100 ms. Thus, this interval is likely to reflect physiological processes within the cerebellum rather than the TMS-stimulus duration. This new evidence supports our earlier claim that the cerebellum is responsible for predictively updating a central state estimate over an interval of about 120-140 ms. Dysfunction of the cerebellum, whether through disease or experimental procedures, leads to motor errors consistent with a loss of knowledge of the true state of the motor system. | 18,855,092 |
Recombinant bactericidal permeability increasing protein (rBPI21) inhibits surgery-induced tumour growth in a murine model of metastatic disease. | Endotoxin (LPS), a cell wall constituent of gram-negative bacteria, is a potent inflammatory stimulus. We demonstrated that laparotomy increases primary tumour growth and experimental lung metastases, implicating endotoxin as a causative factor. We hypothesised that the anti-endotoxin agent, rBPI(21) would block surgery-induced tumour growth. Mammary adenocarcinoma cells were injected into female BALB/c mice to establish lung metastases. Mice were randomised into three groups receiving anaesthesia, laparotomy or laparotomy and rBPI(21) treatment on day 14. Animals were killed on day 19, lungs harvested and blood obtained. Number and size of lung metastases were recorded. Apoptosis, mitosis and microvessel density within metastases were assessed and VEGF measured. Laparotomy increased metastatic growth, decreased tumour cell apoptosis, increased tumour cell proliferation, increased microvessel density and circulating VEGF. LPS blockade by rBPI(21) attenuated this increased growth and decreased proliferation, increased apoptosis, decreased micro-vessel density and circulating VEGF. This suggests that rBPI(21), has clinical potential in attenuating surgery enhanced tumour growth, especially in patients with a history of cancer undergoing laparotomy. | 18,855,097 |
Astrobiological phase transition: towards resolution of Fermi's paradox. | Can astrophysics explain Fermi's paradox or the "Great Silence" problem? If available, such explanation would be advantageous over most of those suggested in literature which rely on unverifiable cultural and/or sociological assumptions. We suggest, instead, a general astrobiological paradigm which might offer a physical and empirically testable paradox resolution. Based on the idea of James Annis, we develop a model of an astrobiological phase transition of the Milky Way, based on the concept of the global regulation mechanism(s). The dominant regulation mechanisms, arguably, are gamma-ray bursts, whose properties and cosmological evolution are becoming well-understood. Secular evolution of regulation mechanisms leads to the brief epoch of phase transition: from an essentially dead place, with pockets of low-complexity life restricted to planetary surfaces, it will, on a short (Fermi-Hart) timescale, become filled with high-complexity life. An observation selection effect explains why we are not, in spite of the very small prior probability, to be surprised at being located in that brief phase of disequilibrium. In addition, we show that, although the phase-transition model may explain the "Great Silence", it is not supportive of the "contact pessimist" position. To the contrary, the phase-transition model offers a rational motivation for continuation and extension of our present-day Search for ExtraTerrestrial Intelligence (SETI) endeavours. Some of the unequivocal and testable predictions of our model include the decrease of extinction risk in the history of terrestrial life, the absence of any traces of Galactic societies significantly older than human society, complete lack of any extragalactic intelligent signals or phenomena, and the presence of ubiquitous low-complexity life in the Milky Way. | 18,855,114 |
Myocardial strain in sub-acute peri-infarct myocardium. | In the absence of additional ischemic insults, the peri-infarct region surrounding the infarct myocardium can recover function. T2 weighted MRI signal is sensitive to edema and used to detect peri-infarct, salvageable myocardium. The main purpose of this study was to investigate the alterations in myocardial strain in the peri-infarct myocardium as compared to normal and infarct myocardium. Comprehensive MRI of the myocardium was performed in five pigs 6-7 days following coronary artery occlusion-reperfusion myocardial injury. MRI included tagged cine images for myocardial strain, T2weighted (T2w)-images and late gadolinium enhancement (LGE) for assessing myocardial viability. Automated signal intensity thresholds were used to define tissue edema and myocardial infarct. Maximum-shortening strains were analyzed in the infarct, peri-infarct and normal myocardial sectors. The results were correlated with triphenyltetrazolium-chloride (TTC) and hemotoxylin-eosin stained tissue images. We found an excellent correlation of LGE with TTC (r = 0.94, P < 0.05). T2w-images markedly overestimated the infarct size (25 +/- 3%). Both the healthy and peri-infarct myocardial sectors had higher myocardial strain than infarct myocardial sectors (P < 0.05). Clear demarcation between infarct and non-infarct myocardium was noted on histology. Peri-infarct myocardium continues to demonstrate T2 signal enhancement to at least 7 days, but this region has preserved mechanical function. T2-weighted imaging and myocardial strain measurements provide complementary information and both may be useful for characterization of the peri-infarct myocardium. | 18,855,121 |
Rates and severity of perforation from implantable cardioverter-defibrillator leads: a 4-year study. | Although recent case reports and one small single-year observational study report a substantially increased rate of perforation with the St. Jude Riata series defibrillator lead, these results have not been externally validated. From 2004 to 2007, 593 implantable cardioverter-defibrillator (ICD) implants were performed by six faculty and 13 fellows at four University of California, San Francisco, CA, USA and affiliate hospitals. An electronic medical records system was systematically searched to identify clinically significant cases of ICD lead dislodgment or perforation. Of 307 (56%) St. Jude leads (all Riata series 6.3- and 7.3-French leads), 188 (29%) Medtronic leads (including 99 Sprint Fidelis 6.6 French leads), and 98 (15%) Guidant/Boston Scientific leads, there were three perforations in 593 cases (0.51%). One perforation occurred with a Medtronic Sprint Fidelis 6949 lead (0.53%), and two with a St. Jude Riata 1581 lead (0.65%). There were no statistically significant differences in perforation or dislodgement rates between manufacturers or lead models (p = NS for all). In both cases of perforation with the St. Jude Riata leads, the lead tip perforated through the pericardium into the pleural space. In our 4-year series of ICD implants, perforation and dislodgement rates were low, similar across all lead makes and models, and well below published and accepted complication rates. Our findings contradict previously-reported higher rates of perforation with the Riata lead. Registry and product performance reports should also classify complications by severity and outcome to provide a more complete assessment of product safety. | 18,855,128 |
Novel visualization of intracardiac pacing lead extractions: methodologies performed within isolated canine hearts. | Several methodologies are typically employed to extract chronically-implanted pacing leads including: laser catheter systems, radio frequency catheters, mechanical cutting catheters, and/or direct traction. In the present study, Visible Heart(R) methodologies were employed to obtain novel internal and external views of such extractions. Utilizing standard cardioplegia procedures, canine hearts (n = 3) with chronically-implanted endocardial pacing leads were explanted to a unique isolated heart apparatus. Modified Krebs-Henseleit buffer allowed for clear endocardial imaging with endoscopic video cameras inserted into the cardiac chambers. Leads were extracted using: (1) laser system with sheath; (2) dissection sheath with incorporated bipolar tungsten electrode; (3) non-powered mechanical sheath; or (4) direct traction. Resultant images provide a novel perspective regarding lead extraction methodologies and the imposed force on an encapsulated lead and on the great vessels and/or heart itself; this understanding may improve the outcome and safety of future lead extractions. | 18,855,129 |
The mechanical environment of bone marrow: a review. | Bone marrow is a viscous tissue that resides in the confines of bones and houses the vitally important pluripotent stem cells. Due to its confinement by bones, the marrow has a unique mechanical environment which has been shown to be affected from external factors, such as physiological activity and disuse. The mechanical environment of bone marrow can be defined by determining hydrostatic pressure, fluid flow induced shear stress, and viscosity. The hydrostatic pressure values of bone marrow reported in the literature vary in the range of 10.7-120 mmHg for mammals, which is generally accepted to be around one fourth of the systemic blood pressure. Viscosity values of bone marrow have been reported to be between 37.5 and 400 cP for mammals, which is dependent on the marrow composition and temperature. Marrow's mechanical and compositional properties have been implicated to be changing during common bone diseases, aging or disuse. In vitro experiments have demonstrated that the resident mesenchymal stem and progenitor cells in adult marrow are responsive to hydrostatic pressure, fluid shear or to local compositional factors such as medium viscosity. Therefore, the changes in the mechanical and compositional microenvironment of marrow may affect the fate of resident stem cells in vivo as well, which in turn may alter the homeostasis of bone. The aim of this review is to highlight the marrow tissue within the context of its mechanical environment during normal physiology and underline perturbations during disease. | 18,855,142 |
Clinical significance and prognostic value of serum sHER-2/neu levels in patients with solid tumors. | The purpose of this study was to determine HER-2/neu in the serum of patients with solid tumors and to investigate its potential usefulness in predicting the clinical course of the disease. At the same time, we compared the ability of serum HER-2/neu, CA15.3, CA12-5, CA19-9, carcino embryonic antigen (CEA), and alpha-feto-protein (AFP) in breast, colorectal, and lung cancer patients. Forty, thirty-six, and twenty-three patients with lung, colon and breast cancer were included in this study, respectively. Serum levels of HER-2/neu, CA15.3, CA12-5, CA19-9, CEA, and AFP were measured. Her-2 neu levels were significantly higher in the breast cancer groups than colorectal and lung cancer and controls groups (P < 0.01). There is no significant difference when compared with others groups (P > 0.05). There was a positive correlation between the HER-2/neu and CA15-3 values in breast cancer groups. We found 0.75(0.59-0.90) for Her-2/neu from the area under the curve (AUC). P-value for breast cancer is 0.003, and we discovered that 9 ng/ml was the best inersection point. In this situation, we calculated that sensitivity was 65.2%, specificity was 100%, positive predictive value was 100%, negative predictive value 75.8%, and accuracy was 83.4%. These findings indicate that serum HER2/neu levels are clinically valuable in monitoring metastatic breast cancer and non-small cell lung cancer patients. Prognosis of breast cancer provides an additional value over the commonly used CA15-3 test. Measurements of levels of serum HER-2/neu provide prognostic and predictive information to the clinician and can especially be used for monitoring metastatic breast cancer patients. Further clinical validation is needed to confirm these findings. | 18,855,148 |
Midgut carcinoid patients display increased numbers of regulatory T cells in peripheral blood with infiltration into tumor tissue. | Our aim was to investigate the immune status of midgut carcinoid patients. Cancer patients generally display suppressed Th1-type immunity that disables mounting of an efficient anti-tumor response. However, little is known about patients with neuroendocrine midgut carcinoids. Circulating regulatory T cells were determined in patient blood by staining for CD4, CD25 and FoxP3 in flow cytometric analysis. T cell proliferation was measured by Alamar Blue in response to polyclonal activation and the regulatory phenotype of patient CD25+ cells was validated by allogeneic stimulation of CFSE labelled responders. Cytokine levels in patient peripheral blood were measured by ELISA and CBA. Tumor infiltrating T cells were analyzed by immunohistochemistry and immunofluorescence. The results demonstrate that midgut carcinoid patients exhibit increased frequencies of circulating Tregs and patient T cells have a decreased proliferative capacity compared to healthy donors. Systemic Th1-promoting cytokines are reduced. Midgut carcinoid tumors display CD4+ and CD8+ T cell infiltration, always in the presence of regulatory CD4+FoxP3+ cells. Midgut carcinoid patients display elevated T regulatory cell numbers and T cell dysfunction. Therapeutic strategies to overcome tumor-induced Th1 immunosuppression are required in combination with anti-tumor vaccinations. | 18,855,160 |
The primary care diagnosis of dementia in Europe: an analysis using multidisciplinary, multinational expert groups. | To explore the extent of variation in the detection of dementia in primary care across Europe, and the potential for the development of European guidelines. A mixture of focus group and adapted nominal group methods involving 23 experts of different disciplines and from eight European countries. The diagnosis of dementia should be 'timely' rather than 'early'. Timeliness has an impact on the patient, on the caregiver, on healthcare professionals, and on society. Ethical and moral issues may interfere with the aim of timely diagnosis. Guidelines may be important for facilitating a timely diagnosis of dementia, but were infrequently used and not even available in three of the eight countries. Referral pathways often depended on health care system characteristics, differing throughout the eight European countries, whilst diagnostic strategies differed due to varied cultural influences. There was consensus that national variations can be reduced and timely diagnosis enhanced by combining simple tests using a systematic stepwise case-finding strategy, in conjunction with a strong infrastructure of multidisciplinary collaboration. This study identified three key themes that should be considered in harmonizing European approaches to the diagnosis of dementia in primary care: (1) a focus on timely diagnosis, (2) the need for the development and implementation of guidelines, and (3) the identification of appropriate referral pathways and diagnostic strategies including multi-professional collaboration. The content of guidelines may be determined by the perspectives of the guideline developers. | 18,855,172 |
Early motherhood and mental health in midlife: a study of British and American cohorts. | Examine the relationship between early age at first birth and mental health among women in their fifties. Analysis of data on women from a British 1946 birth cohort study and the U.S. Health and Retirement Study birth cohort of 1931-1941. In both samples a first birth before 21 years, compared to a later first birth, is associated with poorer mental health. The association between early first birth and poorer mental health persists in the British study even after controlling for early socioeconomic status, midlife socioeconomic status and midlife health. In the U.S. sample, the association becomes non-significant after controlling for educational attainment. Early age at first birth is associated with poorer mental health among women in their fifties in both studies, though the pattern of associations differs. | 18,855,176 |
Validation of a screening instrument for post-traumatic stress disorder in a clinical sample of older adults. | To determine the diagnostic validity of the Post Traumatic Disorder Checklist (PCL) against the 'gold standard' of the Clinician Administered PTSD Scale (CAPS) in a clinical sample of older adults. A cross-sectional validation study: participants were patients (65 years and over) being treated for medical and/or psychiatric conditions in a hospital setting. Participants completed the PCL, measures of mood, cognition, physical health, alcohol use and the CAPS. A receiver operating characteristics curve was constructed to determine the optimal cut-point of the PCL. Analysis of variance was used to examine clinical differences between PTSD cases, sub-threshold cases and the remainder of the sample. Using the recommended cut-point of 50, the PCL had a sensitivity of 0.40, specificity of 0.97 and positive predictive value of 0.57. However, these values changed to 0.90, 0.87 and 0.45, respectively, when the optimal cut-point of 36 was used. With an adjusted cut-point the PCL is an acceptable and brief screening instrument for PTSD in older adults. | 18,855,184 |
Active CD4+ helper T cells directly stimulate CD8+ cytotoxic T lymphocyte responses in wild-type and MHC II gene knockout C57BL/6 mice and transgenic RIP-mOVA mice expressing islet beta-cell ovalbumin antigen leading to diabetes. | CD4+ helper T (Th) cells play crucial role in priming, expansion and survival of CD8+ cytotoxic T lymphocytes (CTLs). However, how CD4+ Th cell's help is delivered to CD8+ T cells in vivo is still unclear. We previously demonstrated that CD4+ Th cells can acquire ovalbumin (OVA) peptide/major histocompatibility complex (pMHC I) and costimulatory CD80 by OVA-pulsed DC (DC(OVA)) stimulation, and then stimulate OVA-specific CD8+ CTL responses in C57BL/6 mice. In this study, we further investigated CD4+ Th cell's effect on stimulation of CD8 CTL responses in major histocompatibility complex (MHC II) gene knockout (KO) mice and transgenic rat insulin promoter (RIP)-mOVA mice with moderate expression of self OVA by using CD4+ Th cells or Th cells with various gene deficiency. We demonstrated that the in vitro DC(OVA)-activated CD4+ Th cells (3 x 10(6) cells/mouse) can directly stimulate OVA-specific CD8+ T-cell responses in wild-type C57BL/6 mice and MHC II gene KO mice lacking CD4+ T cells. A large amount of CD4+ Th cells (12 x 10(6) cells/mouse) can even overcome OVA-specific immune tolerance in transgenic RIP-mOVA mice, leading to CD8+ CTL-mediated mouse pancreatic islet destruction and diabetes. The stimulatory effect of CD4+ Th cells is mediated by its IL-2 secretion and CD40L and CD80 costimulations, and is specifically delivered to OVA-specific CD8+ T cells in vivo via its acquired pMHC I complexes. Therefore, the above elucidated principles for CD4+ Th cells will have substantial implications in autoimmunity and antitumor immunity, and regulatory T-cell-dependent immune suppression. | 18,855,194 |
High values of alpha (CXCL10) and beta (CCL2) circulating chemokines in patients with psoriatic arthritis, in presence or absence of autoimmune thyroiditis. | The possible role of circulating alpha and beta chemokines in psoriatic arthritis is not extensively studied. The aim of the study is to evaluate serum levels of CXCL10, CXCL9 (alpha) and CCL2 (beta) chemokines in a large series of psoriatic arthritis patients, with or without autoimmune thyroid (AT) disorders, and to relate chemokines levels to the clinical phenotype of these patients. Serum levels of CXCL10 and CCL2 were measured in 37 patients with psoriatic arthritis without AT (PsA) and 28 with AT (PsA+AT), and in gender- and age-matched (1:1) controls without (control 1) or with AT (control 2). Serum CXCL10 levels were significantly higher in control 2 than in control 1 (p < 0.001) and in PsA than control 1 or 2 (p < 0.0001). PsA+AT patients have CXCL10 higher than controls 1 and 2 (p < 0.0001, for both) and than PsA (p < 0.001). By defining a high CXCL10 level as a value at least 2 SD above the mean value of the control group (>192 pg/ml), 5% of control 1, 19% of control 2, 42% of PsA and 63% of PsA+AT, had high CXCL10 (p < 0.0001; chi(2)). Serum CCL2 levels were similar in controls 1 and 2. PsA or PsA+AT patients have serum CCL2 levels significantly (p < 0.01, for both) higher than controls 1 and 2. Serum CXCL9 was not significantly different in the study groups. In conclusion, our study demonstrates higher serum levels of CXCL10 and CCL2 chemokines in patients with PsA than in controls. Serum CXCL10 (alpha chemokine) levels in psoriatic arthritis patients are significantly higher in presence of AT. | 18,855,195 |
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