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Signaling pathways open the GAITway to translational control.
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In activated monocytes, Interferon-gamma modulates assembly of a heterotetrameric inhibitor of translation. This is responsive to signaling cascades promoting the induction and activation of death associated protein kinase (DAPK) and consequently zipper-interacting protein kinase (ZIPK). Now Mukhopadhyay et al., in a recent issue of Molecular Cell, show that the kinases themselves are regulated by the same translational silencing they promote thereby providing a negative feedback loop to limit late inflammatory gene expression.
| 19,000,828
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Nucleoporin levels regulate cell cycle progression and phase-specific gene expression.
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The Nup107-160 complex, the largest subunit of the nuclear pore, is multifunctional. It mediates mRNA export in interphase, and has roles in kinetochore function, spindle assembly, and postmitotic nuclear pore assembly. We report here that the levels of constituents of the Nup107-160 complex are coordinately cell cycle-regulated. At mitosis, however, a member of the complex, Nup96, is preferentially downregulated. This occurs via the ubiquitin-proteasome pathway. When the levels of Nup96 are kept high, a significant delay in G1/S progression occurs. Conversely, in cells of Nup96(+/-) mice, which express low levels of Nup96, cell cycle progression is accelerated. These lowered levels of Nup96 yield specific defects in nuclear export of certain mRNAs and protein expression, among which are key cell cycle regulators. Thus, Nup96 levels regulate differential gene expression in a phase-specific manner, setting the stage for proper cell cycle progression.
| 19,000,832
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Heterotrimeric G proteins regulate a noncanonical function of septate junction proteins to maintain cardiac integrity in Drosophila.
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The gene networks regulating heart morphology and cardiac integrity are largely unknown. We previously reported a role for the heterotrimeric G protein gamma subunit 1 (Ggamma1) in mediating cardial-pericardial cell adhesion in Drosophila. Here we show G-oalpha47A and Gbeta13F cooperate with Ggamma1 to maintain cardiac integrity. Cardial-pericardial cell adhesion also relies on the septate junction (SJ) proteins Neurexin-IV (Nrx-IV), Sinuous, Coracle, and Nervana2, which together function in a common pathway with Ggamma1. Furthermore, Ggamma1 signaling is required for proper SJ protein localization, and loss of at least one SJ protein, Nrx-IV, induces cardiac lumen collapse. These results are surprising because the embryonic heart lacks SJs and suggest that SJ proteins perform noncanonical functions to maintain cardiac integrity in Drosophila. Our findings unveil the components of a previously unrecognized network of genes that couple G protein signaling with structural constituents of the heart.
| 19,000,835
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Bmp2 signaling regulates the hepatic versus pancreatic fate decision.
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Explant culture data have suggested that the liver and pancreas originate from common progenitors. We used single-cell-lineage tracing in zebrafish to investigate this question in vivo as well as to analyze the hepatic versus pancreatic fate decision. At early somite stages, endodermal cells located at least two cells away from the midline can give rise to both liver and pancreas. In contrast, endodermal cells closer to the midline give rise to pancreas and intestine, but not liver. Loss- and gain-of-function analyses show that Bmp2b, expressed in the lateral plate mesoderm, signals through Alk8 to induce endodermal cells to become liver. When Bmp2b was overexpressed, medially located endodermal cells, fated to become pancreas and intestine, contributed to the liver. These data provide in vivo evidence for the existence of bipotential hepatopancreatic progenitors and indicate that their fate is regulated by the medio-lateral patterning of the endodermal sheet, a process controlled by Bmp2b.
| 19,000,838
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Computerized counseling for folate knowledge and use: a randomized controlled trial.
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Periconception folate supplementation significantly reduces the risk of neural-tube defects, but few U.S. women start folate supplementation before pregnancy, and the amount of clinician time available to counsel patients about folate is limited. This study evaluated whether computer-assisted counseling and the provision of free folate tablets increases women's knowledge and use of folate supplements. Randomized controlled trial; follow-up began 6 months after enrollment and was completed on average 7 months after enrollment. A total of 446 women, aged 18-45 years, were recruited from two urgent care clinics in San Francisco from March to July 2005 (data collection was completed in 2006; data were analyzed in 2007). Participants received a 15-minute computerized educational session and 200 folate tablets. The primary outcome was the knowledge that folate can prevent birth defects; secondary outcomes included the self-reported use of a folate supplement at follow-up. At follow-up, women in the intervention group were more likely to know that folate prevents birth defects (46% vs 27%, relative risk [RR]=1.72, 95% CI=1.32, 2.23); to know that folate is most important in early pregnancy (36% vs 17%, RR=2.11, 95% CI=1.50, 2.97); and to report the recent use of a folate supplement (32% vs 21%, RR=1.54, 95% CI=1.12, 2.13). A one-time, brief, computerized counseling session about folate with the provision of free folate tablets increased the knowledge and use of folate supplements among women > or =6 months later. NCT00177515.
| 19,000,845
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Mid-life suicide: an increasing problem in U.S. Whites, 1999-2005.
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The overall suicide rate in the U.S. increased by 6% between 1981 and 1986 and declined by 18% between 1986 and 1999. Detailed descriptions of recent trends in suicide are lacking, especially with regard to the method of suicide. Information is needed on the major changes in rates of suicide in specific population groups in recent years (1999-2005). Mortality data came from the Web-based Injury Statistics Query and Reporting System. Suicide trends during 1981-2005 were analyzed by age, race, gender, and method, with an emphasis on increases between 1999 and 2005. Linear regression was used to examine the significance of trends in suicide mortality. The annual percentage change in rates was employed to measure the linear trend in suicide mortality. The suicide rate increased after 1999, due primarily to an increase in suicide among whites aged 40-64 years, whose rate of completed suicide between 1999 and 2005 rose by 2.7% annually for men and by 3.9% annually for women,with increases of 6.3% and 2.3% for poisoning, 2.8% and 19.3% for hanging/suffocation, and 1.5% and 1.9% for firearms for men and women, respectively. Rates did not increase for other age or racial groups [corrected]. The differential increases by age, race, gender, and method underscore a change in the epidemiology of suicide.Whites aged 40-64 years have recently emerged as a new high-risk group for suicide. Although firearms remain the most common method of suicide, the notable increases in suicide by poisoning in men and hanging/suffocation in women deserve prevention attention [corrected].
| 19,000,847
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Complete decontamination and regeneration of DNA purification silica columns.
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Silica columns are among the most used DNA purification systems, allowing a good yield of high-quality nucleic acids without organic extractions. Silica column regeneration protocols reported up to now to remove DNA traces are time-consuming, and their effectiveness on genomic DNA has not been demonstrated. Here we report a very rapid regeneration procedure that ensures no DNA carryover, independent of its size, without impairing column efficiency. The method takes advantage of the improved DNA removal by low concentrations of Triton X-100.
| 19,000,895
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TREP, a novel protein necessary for gliding motility of the malaria sporozoite.
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The invasive stages of parasites of the protozoan phylum Apicomplexa have the capacity to traverse host tissues and invade host cells using a unique type of locomotion called gliding motility. Gliding motility is powered by a sub-membranous actin-myosin motor, and the force generated by the motor is transduced to the parasite surface by transmembrane proteins of the apicomplexan-specific thrombospondin-related anonymous protein (TRAP) family. These proteins possess short cytoplasmic tails that interact with the actin-myosin motor via the glycolytic enzyme aldolase. Gliding motility of the Plasmodium sporozoite, the stage of the malaria parasite that is transmitted by the mosquito to the mammalian host, depends on the TRAP protein. We describe a second protein, herein termed TREP, which also plays a role in the gliding motility of the Plasmodium sporozoite. TREP is a transmembrane protein that possesses a short cytoplasmic tail typical of members of the TRAP family of proteins, as well as a large extracellular region that contains a single thrombospondin type 1 repeat domain. TREP transcripts are expressed predominantly in oocyst stage sporozoites. Plasmodium berghei sporozoites harbouring a disrupted TREP gene have a highly diminished capacity to invade mosquito salivary glands and display a severe defect in gliding motility. We conclude that the gliding motility of the Plasmodium sporozoite in the mosquito depends on at least two proteins, TRAP and TREP.
| 19,000,911
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A proteomic analysis of the aphid Macrosiphum euphorbiae under heat and radiation stress.
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Temperature and solar radiation can be important sources of abiotic stress for small herbivorous insects living in close association with plants. We examined the effects of daily fluctuations of heat and UV radiation on the proteome and performance of winged and wingless morphs of the aphid Macrosiphum euphorbiae. A daily regime of 4h of heat stress at 35 degrees C had more negative effects on the aphid's fitness than a similar period of UV-B stress (11.6kJm(-2) per day), and these effects were most pronounced on wingless aphids. Aphid proteomes as detected on 2-D gels revealed approximately 470 protein spots, with the fluctuating heat stress leading to many more changes than exposure to UV-B. The reduced performance of aphids under heat stress correlated with lower abundance of several enzymes in central pathways of energy metabolism, including the TCA cycle and the respiratory chain. Several exoskeletal proteins were induced or their abundance was increased under high temperature stress, suggesting that cuticle barrier enhancement at molting in response to heat stress is an aphid adaptation to stressful thermal conditions. The proteome of winged aphids was more broadly modulated under stress than that of wingless aphids. Greater homeostatic capabilities as revealed at the proteomic level could explain the higher tolerance of the alate aphid morph to environmental stress and its more stable performance and fitness.
| 19,000,926
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High yielding recombinant Staphylokinase in bacterial expression system--cloning, expression, purification and activity studies.
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Staphylokinase (SAK) is emerging as an important thrombolytic agent. In this report, we describe the cloning, expression, purification and activity studies of the SAK gene of Staphylococcus aureus from a custom synthesised SAK gene. The SAK gene of 411 bp yielded a protein of approximately 15 kDa when expressed under pET21a vector using IPTG as an inducer in BL21 (DE3) pLysE codon Plus cells. The recombinant SAK (rSAK) was soluble in nature and constituted nearly 35% of the total cellular protein as estimated by densitometry scanning. Fermentation studies were carried out to optimize various parameters for maximizing the yield of rSAK and with the optimized medium, the yield of rSAK was nearly 2.8 g/L of fermentation broth, which is highest yield of rSAK expressed in any bacterial system till date. Two simple purification steps of ion-exchange chromatography yielded homogenous rSAK with almost 36% recovery. The purified SAK protein was characterized by MALDI-TOF and by plasminogen activation studies. The rSAK was found to be active by the chromogenic substrate assay method.
| 19,000,928
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Correlates of response to Olanzapine in a North Indian Schizophrenia sample.
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Olanzapine is widely used for the treatment of schizophrenia and is considered a first line medication in India. Along with other factors, the variation in response and side effects to this agent may be accounted for by genetic differences among patients. Olanzapine was administered for 6 weeks to Indian subjects with schizophrenia or schizoaffective disorder (DSM-IV, n=130), as part of an open label study. Intent-to-treat analysis was performed, and 10 polymorphic markers from seven genes (dopamine D1, D2, D3 and D4 receptors, serotonin 2A receptor and the drug-metabolizing enzymes (CYP1A2 and CYP2D6)), together with demographic and clinical variables, were analyzed as potential predictors of response. Olanzapine was efficacious, but significant weight gain was noted. Baseline weight and a 120 bp deletion polymorphism at the dopamine receptor D4 (DRD4) gene were associated with changes in symptom scores. Predictable covariates of treatment response were also noted. These results merit replicate studies.
| 19,000,940
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Evaluation of a telemedicine-based service for the follow-up and monitoring of patients treated with oral anticoagulant therapy.
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The authors have designed and developed a telemedicine-based service for the follow-up and monitoring of patients on oral anticoagulant therapy (OAT) that consists of two phases; the first involving self-testing and the second involving guided self-management. To evaluate the first phase of the protocol, a project was conducted with 108 patients, with a mean age of 72.7 years and a mean treatment time at the start of the study of 55.2 months, divided into two groups: telemedicine and control (conventional procedure). The degree of anticoagulation control was similar in the two groups: individual in-range international normalized ratios (59.2% vs 61.1%; p = 0.55) and individual time within target range (65.7% vs 66.4%; p = 0.85) showed no significant differences. The incidence of adverse events--death (5.5% vs 5.5%; p = 1.0), major hemorrhagic complications (0% vs 1.8%; p = 1.0), minor hemorrhagic complications (7.4% vs 3.7%; p = 0.67), and thromboembolism (1.8% vs 3.7%; p = 1.0)--was also similar, with no significant differences. Acceptability of the change, measured in terms of quality of life (SF-12 and Sawicki questionnaires) and anxiety (state-trait anxiety inventory questionnaire) at the beginning and end of the study period was higher in the telemedicine group, with statistically significant improvements in mental component summary (3.6 vs -6.2; p = 0.02), dissatisfaction (-0.8 vs 0.2; p = 0.001), stress (-0.3 vs 0.05; p = 0.03), limitations (-0.2 vs 0.3; p = 0.005), social problems (-0.1 vs 0.3; p = 0.03), and state anxiety (-2.5 vs 2.3; p = 0.04). Parameters related to costs, such as the mean number per patient of office visits due to OAT (1.7 vs 13.8; p << 0.001) and other office visits (10.1 vs 11.5; p = 0.028), were also more favorable in the telemedicine group, as were additional parameters that enabled an exhaustive evaluation of the service. The positive results obtained indicate that the second phase of the trial can be initiated.
| 19,000,948
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Recursive fuzzy granulation for gene subsets extraction and cancer classification.
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A typical microarray gene expression dataset is usually both extremely sparse and imbalanced. To select multiple highly informative gene subsets for cancer classification and diagnosis, a new Fuzzy Granular Support Vector Machine---Recursive Feature Elimination algorithm (FGSVM-RFE) is designed in this paper. As a hybrid algorithm of statistical learning, fuzzy clustering, and granular computing, the FGSVM-RFE separately eliminates irrelevant, redundant, or noisy genes in different granules at different stages and selects highly informative genes with potentially different biological functions in balance. Empirical studies on three public datasets demonstrate that the FGSVM-RFE outperforms state-of-the-art approaches. Moreover, the FGSVM-RFE can extract multiple gene subsets on each of which a classifier can be modeled with 100% accuracy. Specifically, the independent testing accuracy for the prostate cancer dataset is significantly improved. The previous best result is 86% with 16 genes and our best result is 100% with only eight genes. The identified genes are annotated by Onto-Express to be biologically meaningful.
| 19,000,951
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Detections of arterial wall in sonographic artery images using dual dynamic programming.
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We propose a novel dual dynamic programming (DDP) technique for detecting intimal and adventitial layers of the common carotid artery of the B-mode sonographic images. This method embeds the anatomic knowledge into its structure so that the robustness against the speckles is increased. Moreover, it inherits the property of getting the optimal solution as the traditional dynamic programming (TDP). Our experimental study shows that the DDP technique achieves a detection performance comparable to manual tracing achieved by physicians. The results demonstrate that it has the potential to perform qualitatively better than applying TDP twice in intimal and adventitial layer detection on sonographic B-mode images.
| 19,000,960
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Anti-atherogenic and anti-inflammatory properties of high-density lipoprotein are affected by specific antibodies in systemic lupus erythematosus.
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To determine whether antibodies against high-density lipoprotein (aHDL) and apolipoprotein A-I (aApo A-I) interfere with the anti-atherogenic functions of high-density lipoprotein (HDL) and relate to disease activity and damage in SLE. Seventy-seven SLE patients were compared with an age- and sex-frequency matched control group. Immunoglobulin G (IgG) aHDL, IgG aApoA-I, soluble vascular cell and intracellular cell adhesion molecules (VCAM-1 and ICAM-1, respectively) were measured by ELISA, paraoxonase (PON) activity by spectrophotometry, nitric oxide (NOx) metabolites by the Griess reaction, and total anti-oxidant capacity (TAC) by chemiluminescence. Compared with controls, SLE patients showed higher titres of IgG aHDL (P < 0.0001) and IgG aApo A-I (P < 0.0001), lower PON activity (P < 0.0001), increased NOx (P < 0.0001), VCAM-1 (P < 0.0001) and ICAM-1 (P = 0.0008) and lower TAC (P = 0.0006). Titres of IgG aHDL positively correlated with IgG aApo A-I (r = 0.64, P < 0.0001), NOx (r = 0.32, P = 0.007), inversely correlated with PON activity (r = -0.34, P = 0.002) and TAC (r = -0.43, P = 0.0004) and were independently associated with ICAM-1 (t = 3.509, P = 0.001). IgG aApo A-I titres correlated positively with NO (r = 0.37, P = 0.007), inversely with PON activity (r = -0.31, P = 0.006), TAC (r = -0.47, P < 0.0001) and were independently associated with HDL (t = -2.747, P = 0.008) and VCAM-1 (t = 3.311, P = 0.002), the latter alongside NOx (T = 2.271, P = 0.02). Elevated titres of IgG aHDL and IgG aApo A-I and reduced PON activity related to increased disease score (BILAG) and damage index (SLICC/ACR DI). In SLE, IgG aHDL and aApo A-I associate with disease activity and damage and interfere with the anti-oxidant and anti-inflammatory functions of HDL favouring atherogenesis.
| 19,000,993
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Serum intact parathyroid hormone levels predict hospitalisation for heart failure.
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To assess whether circulating levels of intact parathyroid hormone (intact PTH) in outpatients predict hospitalisation for heart failure (HF). Eighty-eight consecutive outpatients with HF were enrolled in the study. The independent association between intact PTH and hospitalisation for HF was assessed using Cox regression analysis. Mean (SD) serum intact PTH levels significantly increased as New York Heart Association classes increased (I: 40 (21), II: 55 (24), III: 76 (46), IV: 131 (45) pg/ml). The receiver operating characteristic (ROC) curves showed intact PTH levels >or=47 pg/ml to be the optimal cut-off points for hospitalisation for HF, with sensitivity 87%, specificity 71% and area under the ROC curve 0.82 (95% CI 0.72 to 0.91). After adjustment for variables accepted to be predictors for hospitalisation due to HF (age, gender, hypertension, diabetes mellitus, atrial fibrillation, ischaemic heart disease, left ventricular ejection fraction, B-type natriuretic peptide, estimated glomerular filtration rate and cardiac drugs), intact PTH levels >or=47 pg/ml were associated with a hazard ratio of 7.13 for hospitalisation for HF (95% CI 1.79 to 28.4). Serum intact PTH levels obtained in outpatients with HF were shown to be an independent predictor of hospitalisation for HF.
| 19,001,003
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The role of primary care in promoting children's physical activity.
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Regular physical activity enhances health during childhood and adolescence and is important in setting the stage for participation in physical activity across the lifespan. Physician-patient interactions during childhood and adolescence provide important opportunities for clinicians to influence physical activity behaviours. This article reviews current physical activity recommendations for youth and the wide range of health benefits provided to youth from engaging in regular physical activity. It also outlines a practical counselling model, the 5As approach, that can guide clinical counselling for physical activity, and reviews how an increasingly important model of practice organisation, the Care Model, can be used to promote physical activity in children and adolescents. Family, social and environmental influences on child and adolescent physical activity are also addressed.
| 19,001,016
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A comparison of Canadian pediatric resident career plans in 1998 and 2006.
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Studies of pediatric resident career plans and preferences help to forecast changes in the demographic profile and practice patterns of North American pediatricians, providing insights that can guide child health care and medical education policy making. With this study we aimed to compare 4 aspects of Canadian pediatric resident career plans in 1998 and 2006: (1) weekly work hours; (2) scope of practice; (3) professional activities; and (4) community size. Canadian pediatric residents were invited to participate in a national cross-sectional survey to explore career plans and preferences in 1998 (mailing) and 2006 (on-line). Response rates were 69% in 1998 and 52% in 2006. In both survey years, the majority of respondents were female (69% and 73%, respectively). Overall, residents planned to work a similar number of weekly hours in both survey years (47.8 vs 48.8). Women planned to work significantly fewer hours than men; this gap was wider in 2006 than in 1998 (1998: 2.8 fewer hours; 2006: 7.8 fewer hours). After adjusted analysis, the association between proportion of time in primary care and study year became significant; however, time in consultant general or subspecialty pediatrics remained nonsignificantly changed. Residents planned to spend less time in clinical work in 2006 than 1998 (64.4% vs 58.1%), and more planned to work and reside in metropolitan areas (68% vs 78% of decided respondents). Between 1998 and 2006, there was no overall change in the number of hours that Canadian pediatric residents planned to work, but the gender gap widened because of an increase in planned weekly work hours among men. The results also suggest that new strategies may be needed to improve future pediatrician availability in small communities by addressing barriers to nonmetropolitan practice, especially for women.
| 19,001,036
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Increased reverse triiodothyronine is associated with shorter survival in independently-living elderly: the Alsanut study.
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Increased reverse tritiodothyronine (T(3)) used to be described as a part of euthyroid sick syndrome (ESS). It was demonstrated to be associated with increased mortality in acutely ill patients. It can also be found with low or normal T(3) in non-severely ill subjects but its significance remains unclear. The Alsanut study included a representative sample of 440 independently-living subjects aged 65 or over constituted between January 1988 and September 1989. Past and current medical history and nutritional data were collected at inclusion. Baseline thyroid hormone (TSH, FT(4), FT(3) and rT(3)) serum levels were measured. Life status was determined on 1 December 2005. Of the 374 elderly subjects included in the final analysis, 52 had abnormal TSH (43 with hyperthyroidism, nine with hypothyroidism) and 80.7% had died by 1 December 2005. There was no statistical difference in survival between subjects according to thyroid function (P=0.54). Of the 322 elderly subjects with normal TSH, mortality rate was 81.1%. ESS was found in 3.4%, whereas 8.1% of the participants displayed elevated rT(3) with normal FT(3). Time to death was strongly related to rT(3) (P<0.0001) and FT(3) (P<0.0001) in a univariate analysis. After adjusting for other confounding variables, rT(3) was the only thyroid hormone associated with shorter survival (P=0.014). RT(3) was the only thyroid hormone associated with shorter survival in a representative population of independently-living elderly. In these subjects, isolated elevated rT(3) might be an equivalent of ESS, reflecting declining health.
| 19,001,060
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Borrelia burgdorferi infection-associated surface proteins ErpP, ErpA, and ErpC bind human plasminogen.
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Host-derived plasmin plays a critical role in mammalian infection by Borrelia burgdorferi. The Lyme disease spirochete expresses several plasminogen-binding proteins. Bound plasminogen is converted to the serine protease plasmin and thereby may facilitate the bacterium's dissemination throughout the host by degrading extracellular matrix. In this work, we demonstrate plasminogen binding by three highly similar borrelial outer surface proteins, ErpP, ErpA, and ErpC, all of which are expressed during mammalian infection. Extensive characterization of ErpP demonstrated that this protein bound in a dose-dependent manner to lysine binding site I of plasminogen. Removal of three lysine residues from the carboxy terminus of ErpP significantly reduced binding of plasminogen, and the presence of a lysine analog, epsilon-aminocaproic acid, inhibited the ErpP-plasminogen interaction, thus strongly pointing to a primary role for lysine residues in plasminogen binding. Ionic interactions are not required in ErpP binding of plasminogen, as addition of excess NaCl or the polyanion heparin did not have any significant effect on binding. Plasminogen bound to ErpP could be converted to the active enzyme, plasmin. The three plasminogen-binding Erp proteins can also bind the host complement regulator factor H. Plasminogen and factor H bound simultaneously and did not compete for binding to ErpP, indicating separate binding sites for both host ligands and the ability of the borrelial surface proteins to bind both host proteins.
| 19,001,079
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Deletion of Shp2 tyrosine phosphatase in muscle leads to dilated cardiomyopathy, insulin resistance, and premature death.
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The intracellular signaling mechanisms underlying the pathogenesis of cardiac diseases are not fully understood. We report here that selective deletion of Shp2, an SH2-containing cytoplasmic tyrosine phosphatase, in striated muscle results in severe dilated cardiomyopathy in mice, leading to heart failure and premature mortality. Development of cardiomyopathy in this mouse model is coupled with insulin resistance, glucose intolerance, and impaired glucose uptake in striated muscle cells. Shp2 deficiency leads to upregulation of leukemia inhibitory factor-stimulated phosphatidylinositol 3-kinase/Akt, Erk5, and Stat3 pathways in cardiomyocytes. Insulin resistance and impaired glucose uptake in Shp2-deficient mice are at least in part due to impaired protein kinase C-zeta/lambda and AMP-kinase activities in striated muscle. Thus, we have generated a mouse line modeling human patients suffering from cardiomyopathy and insulin resistance. This study reinforces a concept that a compound disease with multiple cardiovascular and metabolic disturbances can be caused by a defect in a single molecule such as Shp2, which modulates multiple signaling pathways initiated by cytokines and hormones.
| 19,001,090
|
Relationship between the presence of practice systems and the quality of care for depression.
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A valid measure of practice systems for improving chronic disease care is needed as a guide for both improvement and public accountability. We tested whether a new survey measure of the presence of practice systems (the PPC-R) is associated with performance measure rates for depression among 40 medical groups in Minnesota. These PPC-R scores were compared with standardized medical group measures of antidepressant persistence. Only 54% of potentially important systems were present, and there was high variability. However, there was a positive correlation between systems and quality on the 90-day measure of antidepressant persistence, both overall (r = .33, P = .04) and for the Chronic Care Model domains of decision support (r = .38, P = .02) and delivery system redesign (r = .31, P = .05). Thus, practice systems overall and several domains of the Chronic Care Model appear to be associated with higher quality care for depression. This questionnaire may help practices identify particular systems to improve.
| 19,001,099
|
Vancomycin ototoxicity: a reevaluation in an era of increasing doses.
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Nephrotoxicity and ototoxicity have historically been documented as relatively rare complications of vancomycin monotherapy. Recent reports have linked aggressive vancomycin dosing strategies to significant risks of nephrotoxicity. We evaluated the rate of high-frequency hearing loss detected by audiometry for patients on vancomycin therapy. For this purpose, we used retrospective case-control analysis of audiometry results for patients on vancomycin therapy for whom baseline and follow-up exams were available. Analysis of 89 patients for whom audiograms were performed after an average of 27 days of vancomycin therapy showed a 12% rate of high-frequency hearing loss, with a trend in univariate analysis toward a higher rate with advanced age. The mean of the highest vancomycin trough levels for both patients with worsening audiograms and those without worsening audiograms was 19 mg/liter. Regression tree modeling demonstrated that for patients <53 years old, the rate of high-frequency hearing loss detected by audiogram was 0%, while for patients >53 years old, the incidence was 19% (P = 0.008). We conclude that a significant rate of high-frequency hearing loss in older patients receiving vancomycin monotherapy was detected by audiometry. While these data urge caution against continued indiscriminate vancomycin dose escalation to treat infections caused by Staphylococcus aureus strains for which vancomycin MICs are 2 mg/liter, further prospective studies are needed to determine the clinical significance and reversibility of these effects.
| 19,001,107
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Maternal smoking, preeclampsia, and infant health outcomes in New York City, 1995-2003.
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A number of previous studies have reported an inverse association between maternal smoking and preeclampsia. Additionally, some have suggested that smokers who develop preeclampsia have worse maternal and fetal outcomes than nonsmokers who develop preeclampsia. The authors examined the relation of smoking to preeclampsia among 674,250 singleton pregnancies in New York City between 1995 and 2003. Although smoking was associated with a reduced risk of preeclampsia overall (adjusted odds ratio = 0.88, 95% confidence interval: 0.82, 0.94), no association was found for preeclampsia superimposed on chronic hypertension (adjusted odds ratio = 1.04, 95% confidence interval: 0.90, 1.21). Furthermore, the apparent protection conferred by maternal smoking was restricted to women aged < or =30 years. Contrary to previous reports, the authors found evidence of a negative interaction between smoking and preeclampsia with respect to preterm delivery and birth weight; smokers who developed preeclampsia had a lower risk of preterm delivery, and a lower adjusted mean difference in birth weight, than would have been expected based on the independent effects of smoking and preeclampsia. These data suggest that smoking is only protective against preeclampsia without pre gestational hypertension, and even then principally among younger women. Additionally, smokers who develop these disorders have no increased risk of adverse birth outcomes relative to nonsmokers who develop the same conditions.
| 19,001,134
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The mechanism of anti-CTLA-4 activity and the negative regulation of T-cell activation.
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The survival rate of patients diagnosed with late-stage melanoma is poor--only 5%-10%. Enlisting the immune system in the fight against cancers such as melanoma could help improve the prognosis of these patients. Data have shown that melanocyte proteins make good targets for immune system-based therapy in this disease. However, self-tolerance, which develops to inhibit autoimmune attack, makes this strategy difficult. Two proteins on the surface of T cells--CD28 and cytotoxic T-lymphocyte antigen 4 (CTLA-4)--play important roles in the regulation of immune activation and tolerance. CD28 provides positive modulatory signals in the early stages of an immune response, while CTLA-4 signaling inhibits T-cell activation, particularly during strong T-cell responses. CTLA-4 blockade using anti-CTLA-4 monoclonal antibody therapy has great appeal because suppression of inhibitory signals results in the generation of an antitumor T-cell response. Both clinical and preclinical data indicate that CTLA-4 blockade results in direct activation of CD4+ and CD8+ effector cells, and anti-CTLA-4 monoclonal antibody therapy has shown promise in a number of cancers, particularly melanoma. Interestingly, the occurrence of adverse events among patients treated with CTLA-4 blockade helps shed light on the mechanism of action of anti-CTLA-4 monoclonal antibodies. Most adverse events involve immune-related toxicity to the skin and gastrointestinal tract. Major gastrointestinal toxicity develops in up to 21% of treated patients, and while an objective response occurs in approximately 36% of melanoma patients who develop enterocolitis with treatment, an objective response is found in only 11% of patients who do not experience this adverse reaction.
| 19,001,145
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Patent foramen ovale: diagnosis with multidetector CT--comparison with transesophageal echocardiography.
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To evaluate the clinical feasibility and accuracy of 64-section multidetector computed tomography (CT) compared with transesophageal echocardiography (TEE) for diagnosis of a patent foramen ovale (PFO). Institutional review board approval was obtained for this retrospective study. The study included 152 consecutive stroke patients (mean age, 61.7 years; 98 men, 54 women) who underwent both cardiac multidetector CT and TEE. Electrocardiographically gated cardiac CT was performed with a 64-section CT scanner by using a saline-chaser contrast agent injection technique. A contrast agent jet from the contrast agent-filled left atrium (LA) to the saline-filled right atrium (RA) and channel-like appearance of the interatrial septum (IAS) were evaluated on axial and oblique sagittal CT images. Two-dimensional and Doppler TEE were performed to detect PFO. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of CT were obtained with TEE as the reference standard. A PFO was present in 26 patients at TEE. On CT images, a left-to-right contrast agent jet toward the inferior vena cava was noted in 21 patients (sensitivity, 73.1%; specificity, 98.4%; PPV, 90.5%; NPV, 94.7%). Channel-like appearance of the IAS was detected in 38 patients (sensitivity, 76.9%; specificity, 85.7%; PPV, 52.6%; NPV, 94.7%). Channel-like appearance of the IAS was noted in all patients who had a contrast agent jet. A contrast agent jet from LA to RA toward the inferior vena cava with channel-like appearance of the IAS on CT images confirms the presence of a PFO.
| 19,001,153
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TDP-43 in cerebrospinal fluid of patients with frontotemporal lobar degeneration and amyotrophic lateral sclerosis.
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Recently, TAR DNA-binding protein 43 (TDP-43) was identified as the major component of ubiquitin-positive tau-negative neuronal and glial inclusions in the most common form of frontotemporal lobar degeneration (FTLD) and in amyotrophic lateral sclerosis (ALS). It was demonstrated that different TDP-43 profiles correspond to clinical phenotypes of FTLD or ALS subgroups, and the differential diagnostic potential of TDP-43 was suggested. To examine TDP-43 in cerebrospinal fluid (CSF) and to analyze whether it could serve as a diagnostic marker. We characterized CSF TDP-43 by immunoblot using different TDP-43 antibodies and determined the relative TDP-43 levels in CSF samples from patients. Academic research. Twelve patients with FTLD, 15 patients with ALS, 9 patients with ALS plus FTLD, 3 patients with ALS plus additional signs of frontal disinhibition, and 13 control subjects. Results of TDP-43 immunoblot. Polyclonal TDP-43 antibodies recognized a 45-kDa band in all analyzed samples. Two monoclonal and N-terminus-specific antibodies did not detect any specific bands, but C-terminus-specific antibodies detected a 45-kDa band and additional bands at approximately 20 kDa in all CSF samples. Relative quantification of 45-kDa bands revealed significant differences among the diagnostic groups (P =.046). Specifically, patients with ALS (P =.03) and FTLD (P =.02) had higher TDP-43 levels than controls but with a prominent overlap of values. Although there is no evidence of pathologically altered TDP-43 proteins in CSF, TDP-43 levels in CSF might aid in characterizing subgroups of patients across the ALS and FTLD disease spectrum.
| 19,001,167
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Deletion of inducible nitric oxide synthase provides cardioprotection in mice with 2-kidney, 1-clip hypertension.
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Inducible NO synthase (iNOS) has been implicated in the pathogenesis of hypertension and target organ damage. We hypothesized that induction of iNOS contributes to left ventricular (LV) hypertrophy and dysfunction in mice with 2-kidney, 1-clip hypertension. Deletion of iNOS diminishes oxidative stress, thereby attenuating LV hypertrophy and enhancing cardiac performance. 2-Kidney, 1-clip hypertension was induced in mice lacking iNOS and wild-type controls (C57BL/6J). Sham-clipped mice served as controls. Systolic blood pressure was measured weekly by tail cuff. Left ventricular ejection fraction (by echocardiography) and cardiac response (maximum and minimum dP/dt, as well as an indicator of isovolumic contraction) to isoproterenol (50 ng per mouse, i.v.) were studied at the end of the experiment. 4-Hydroxy-2-nonenal (a byproduct of lipid peroxidation and an indicator of oxidative stress) was measured by immunohistochemical staining. gp91(phox), endothelial NO synthase, and iNOS protein expression were determined by Western blot. We found that systolic blood pressure, LV weight, myocyte cross-sectional area, interstitial collagen fraction, ejection fraction, and cardiac response to isoproterenol did not differ between strains with sham clipping. 2-Kidney, 1-clip hypertension increased systolic blood pressure, LV weight, myocyte cross-sectional area, and interstitial collagen fraction similarly in both strains. However, in mice lacking iNOS, maximum and minimum dP/dt, as well as an indicator of isovolumic contraction, markedly increased in response to isoproterenol, associated with decreased cardiac 4-hydroxy-2-nonenal expression and urinary nitrate/nitrite. We concluded that deletion of iNOS does not seem to play a significant role in preventing 2-kidney, 1-clip hypertension-induced hypertension and cardiac hypertrophy; however, it does enhance preservation of cardiac function, probably because of a reduction of iNOS-induced oxidative stress.
| 19,001,185
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Somatostatin 2A receptor-expressing presympathetic neurons in the rostral ventrolateral medulla maintain blood pressure.
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Bulbospinal neurons in the rostral ventrolateral medulla (RVLM) are critical for the maintenance of sympathetic vasomotor tone and normal cardiovascular reflex function. So far, selectively eliminating/inhibiting distinct subpopulations of RVLM neurons has not significantly altered arterial pressure. Here we show that RVLM presympathetic neurons that express somatostatin 2A receptors are essential for maintaining and potentially generating sympathetic vasomotor tone. Combined immunocytochemistry and in situ hybridization were used to map the expression of somatostatin receptors 1, 2A, 2B, 3, and 4 (sst1 through 4, respectively) in the rat RVLM. sst1 and sst2B were absent; sst3 and sst4 were sparse. However, sst2A was found postsynaptically and detected in 35+/-5% of bulbospinal RVLM neurons a population that included 54+/-4% of catecholaminergic and 30+/-3% of enkephalinergic neurons. Bilateral microinjection into the RVLM of either somatostatin or the receptor-selective agonist lanreotide evoked dramatic, dose-dependent sympathoinhibition, hypotension, and bradycardia that were blocked by the sst2 receptor antagonist BIM-23627 in anesthetized rats. Bilateral RVLM microinjection of somatostatin also attenuated chemoreceptor and somatosympathetic reflex function. Somatostatin only eliminated the first sympathoexcitatory peak evoked by somatosympathetic reflex activation, whereas muscimol abolished both excitatory peaks providing functional evidence that the activity of only a subpopulation of RVLM presympathetic neurons is inhibited by somatostatin. We suggest that the subpopulation of bulbospinal RVLM neurons that expresses the sst2A receptor sets sympathetic vasomotor output. These neurons are essential for maintaining resting blood pressure under anesthesia and contribute to adaptive reflexes mediated through the RVLM.
| 19,001,189
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Vitamin B12 and folate and the risk of anemia in old age: the Leiden 85-Plus Study.
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Screening for deficiencies in vitamin B(12) and folate is advocated to prevent anemia in very elderly individuals. However, the effects of vitamin B(12) and folate deficiency on the development of anemia in old age have not yet been established. The current study is embedded in the Leiden 85-Plus Study, a population-based prospective study of subjects aged 85 years. Levels of vitamin B(12), folate, and homocysteine were determined at baseline. Hemoglobin levels and mean corpuscular volume (MCV) were determined annually during 5 years of follow-up. We analyzed data from 423 subjects who did not use any form of cyanocobalamin, hydroxocobalamin, or folic acid supplementation, neither at baseline nor during follow-up. Folate deficiency (<7 nmol/L; n = 34) and elevated homocysteine levels (>13.5 mumol/L; n = 194) were associated with anemia at baseline (adjusted odds ratio [OR], 2.44; 95% confidence interval [CI], 1.06-5.61; and adjusted OR, 1.82; 95% CI, 1.08-3.06, respectively), but vitamin B(12) deficiency (<150 pmol/L; n = 68) was not (adjusted OR, 1.51; 95% CI, 0.79-2.87). Furthermore, vitamin B(12) deficiency was not associated with the development of anemia during follow-up (adjusted HR, 0.92; 95% CI, 0.46-1.82) or with changes in MCV (adjusted linear mixed model; P = .77). Both folate deficiency and elevated homocysteine levels were associated with the development of anemia from age 85 years onward (adjusted HR, 3.33; 95% CI, 1.55-7.14; and adjusted HR, 1.70; 95% CI, 1.01-2.88, respectively), but not with an increase in MCV over time (P > .30). In the general population of very elderly individuals, anemia in 85-year-old subjects is associated with folate deficiency and elevated homocysteine levels but not with vitamin B(12) deficiency.
| 19,001,201
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Plaque radiotherapy for juxtapapillary choroidal melanoma overhanging the optic disc in 141 consecutive patients.
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To evaluate tumor control with plaque radiotherapy for juxtapapillary choroidal melanoma that overhangs the optic disc. Retrospective medical record review of 141 consecutive patients with data on complications of treatment, final visual acuity, visual loss, enucleation, tumor recurrence, metastasis, and death. The median patient age was 61 years. Presenting symptoms included reduced visual acuity in 72 eyes (51%), photopsia in 14 (10%), and visual field defect in 18 (13%); 35 patients (25%) were asymptomatic. The median tumor basal diameter was 11 mm and the median thickness was 5.2 mm. The tumor overhung 50% or less of the disc in 88 eyes (62%) and more than 50% of the disc in 53 eyes (38%). In 19 cases (13%), the tumor overhung the entire disc. All patients were treated with plaque radiotherapy, using a notched design in 126 eyes (89%) and a round design in 14 eyes (10%), with iodine 125 in 132 eyes (94%) and cobalt 60 in 9 eyes (6%). The median radiation dose to the tumor apex was 8500 cGy. Adjuvant transpupillary thermotherapy was used in 54 eyes (39%). During a mean follow-up of 56 months, complications included nonproliferative retinopathy in 61 eyes (51%), proliferative retinopathy in 26 (22%), maculopathy in 44 (37%), papillopathy in 57 (48%), neovascular glaucoma in 23 (19%), and vitreous hemorrhage in 48 (40%). A final visual acuity of 20/200 or worse was measured in 72 eyes (77%), and visual loss of more than 5 Snellen lines occurred in 59 eyes (63%). Enucleation was necessary in 27 eyes (23%). Tumor recurrence was found in 12 eyes (10%). Metastasis developed in 15 patients (13%) and death in 4 cases (3%). Using plaque radiotherapy for choroidal melanoma overhanging the optic disc, local tumor control was achieved in 90% of cases. Tumor and radiation effects led to poor visual acuity in 77% of eyes. The metastatic rate was 13% and the mortality rate was 3%.
| 19,001,218
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Roles of PCNA-binding and ubiquitin-binding domains in human DNA polymerase eta in translesion DNA synthesis.
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Treatment of yeast and human cells with DNA-damaging agents elicits Rad6-Rad18-mediated monoubiquitination of proliferating cell nuclear antigen (PCNA) at its Lys-164 residue [ubiquitin (Ub)-PCNA], and this PCNA modification is indispensable for promoting the access of translesion synthesis (TLS) polymerases (Pols) to PCNA. However, the means by which K164-linked Ub modulates the proficiency of TLS Pols to bind PCNA and take over synthesis from the replicative Pol has remained unclear. One model that has gained considerable credence is that the TLS Pols bind PCNA at 2 sites, to the interdomain connector loop via their PCNA-interacting protein (PIP) domain and to the K164-linked Ub moiety via their Ub-binding domain (UBD). Specifically, this model postulates that the UBD-mediated binding of TLS Pols to the Ub moiety on PCNA is necessary for TLS. To test the validity of this model, we examine the contributions that the PIP and Ub-binding zinc finger (UBZ) domains of human Poleta make to its functional interaction with PCNA, its colocalization with PCNA in replication foci, and its role in TLS in vivo. We conclude from these studies that the binding to PCNA via its PIP domain is a prerequisite for Poleta's ability to function in TLS in human cells and that the direct binding of the Ub moiety on PCNA via its UBZ domain is not required. We discuss the possible role of the Ub moiety on PCNA in TLS.
| 19,001,268
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Impact of XIAP protein levels on the survival of myeloma cells.
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XIAP is the best characterized and the most potent direct endogenous caspase inhibitor and is considered a key actor in the control of apoptotic threshold in cancer cells. In this report, we specifically addressed XIAP regulation and function in myeloma cells. XIAP and its endogenous inhibitor XAF-1 protein levels and their regulation were assessed by immunoblot analysis in myeloma cell lines or primary myeloma cells. XIAP knockdown by RNA interference was used to evaluate XIAP impact on in vitro drug sensitivity and in vivo tumor growth. Our results indicate that myeloma cells expressed high levels of XIAP protein that were tightly regulated during growth factor stimulation or stress condition. Of note, an increased XIAPlevel was evidenced during the blockade of the canonical cap-dependent translation by the mTOR inhibitor rapamycin, supporting the hypothesis of a functional IRES sequence in XIAP mRNA. In addition, caspase-mediated XIAP cleavage correlated to an apoptotic process occurring upon cell treatment with the proteasome inhibitor bortezomib. Importantly, XIAP knockdown using RNA interference enhanced drug sensitivity and decreased tumor formation in NOD/SCID mice. Finally, myeloma cells also expressed the XIAP inhibitor XAF-1 that interacted with XIAP in viable myeloma cells. Altogether, our data argue for a delicate control of XIAP function in myeloma cells and stimulate interest in targeting XIAP in myeloma treatment.
| 19,001,278
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Progressive loss of DNA methylation releases epigenetic gene silencing from a tandemly repeated maize Myb gene.
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Maize pericarp color1 (p1) gene, which regulates phlobaphene biosynthesis in kernel pericarp and cob glumes, offers an excellent genetic system to study tissue-specific gene regulation. A multicopy p1 allele, P1-wr (white pericarp/red cob) is epigenetically regulated. Hypomethylation of P1-wr in the presence of Unstable factor for orange1 (Ufo1), leads to ectopic pigmentation of pericarp and other organs. The Ufo1-induced phenotypes show incomplete penetrance and poor expressivity: gain of pigmentation is observed only in a subset of plants carrying Ufo1 mutation, and the extent of pigmentation is highly variable. We show that Ufo1 induces progressive hypomethylation of P1-wr repeats over generations. After five generations of exposure to Ufo1, a 30-40% decrease in CG and CNG methylation was observed in an upstream enhancer and an intron region of P1-wr. Interestingly, such hypomethylation correlated with an increase in penetrance of the Ufo1-induced pigmentation phenotype from approximately 27 to 61%. Expressivity of the Ufo1-induced phenotype also improved markedly as indicated by increased uniformity of pericarp pigmentation in the later generations. Furthermore, the poor expressivity of the Uo1 is associated with mosaic methylation patterns of the P1-wr upstream enhancer in individual cells and distinct P1-wr gene copies. Finally, comparison of methylation among different tissues indicated that Ufo1 induces rapid CG and CNG hypomethylation of P1-wr repeats during plant development. Together, these data indicate that the poor penetrance and expressivity of Ufo1-induced phenotypes is caused by mosaicism of methylation, and progressive mitotic hypomethylation leads to improved meiotic heritability of the mutant phenotype. In duplicated genomes like maize, loss of an epigenetic regulator may produce mosaic patterns due to redundancy of epigenetic regulators and their target sequences. We show here that multiple developmental cycles may be required for complete disruption of suppressed epigenetic states and appearance of heritable phenotypes.
| 19,001,287
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Physicians' experiences with BRCA1/2 testing in community settings.
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We surveyed a national sample of nonacademic physicians who ordered BRCA1/2 testing to understand their implementation of genetic testing and to assess recommendations for surveillance and cancer risk management of women with positive test results. We surveyed physicians (N = 611 of 1,050; response rate, 58.2%) practicing in nonacademic settings who ordered BRCA1/2 testing during 2004 to 2005. We described physicians' experiences with testing and used multivariable regression models to identify factors associated with more complete counseling and with recommendations for cancer risk management for a BRCA1 mutation carrier. Most physicians (68.2%) usually or always discussed six counseling items before testing. In adjusted analyses, physicians who were assisted by genetic counselors, nurse geneticists, or others (v counseling by themselves), those who spent more than 60 minutes in counseling, and medical oncologists (v surgeons or geneticists) were more likely to discuss all six items (all P < .05). A total of 61.4% of physicians would recommend bilateral prophylactic mastectomy to a 38-year-old BRCA1 mutation carrier who had completed childbearing. After adjustment, geneticists and gynecologists were less likely than medical oncologists and surgeons to recommend prophylactic mastectomy (P < .001), as were physicians in the Northeast versus those in other regions of the United States (P = .01). Community-based physicians seem to be successfully incorporating BRCA1/2 testing into their practices. Physicians' recommendations for surveillance of mutation carriers are generally consistent with practice guidelines, yet recommendations for preference-based procedures such as prophylactic mastectomy vary by physician characteristics such as specialty and geographic region. The providers whom patients see for testing may contribute to variations in prophylactic treatments.
| 19,001,322
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Association of serum interleukin-7 levels with the development of acute graft-versus-host disease.
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Morbidity from acute graft-versus-host disease (GVHD) limits the success of allogeneic hematopoietic stem-cell transplantation (HSCT) to treat malignancy. Interleukin-7 (IL-7), the principal homeostatic cytokine for T cells, is required for acute GVHD in murine models. In contrast to inflammatory cytokines (eg, IL-2, tumor necrosis factor alpha), IL-7 has not been studied extensively in the clinical transplant setting relative to its relationship with acute GVHD. We evaluated the association of serum IL-7 levels with acute GVHD in 31 patients who were uniformly treated in a prospective clinical trial with reduced-intensity allogeneic HSCT from human leukocyte antigen-identical siblings. GVHD prophylaxis consisted of cyclosporine and methotrexate. Serum IL-7 levels and lymphocyte populations were determined at enrollment, the day of transplantation before the allograft infusion, and at specified intervals through 12 months post-transplantation. As expected, IL-7 levels were inversely correlated with T-cell populations (P < .00001). Acute GVHD was significantly associated with higher IL-7 levels at day +7 (P = .01) and day +14 (P = .00003) post-transplantation as well as with the allograft CD34(+) cell dose (P = .01). IL-7 levels at day +14 also correlated with the severity of acute GVHD (P < .0001). In logistic regression models, these factors were highly sensitive (up to 86%) and specific (100%) for classifying whether patients developed acute GVHD. These data support preclinical observations that IL-7 plays a critical role in inducing acute GVHD and provide a rational basis for novel approaches to prevent and treat acute GVHD through modulation of the IL-7 pathway.
| 19,001,329
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Simulation of neuronal death and network recovery in a computational model of distributed cortical activity.
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The authors utilize a model of activity-dependent neuronal plasticity to study the interplay between synaptogenesis, neuronal death, and neurogenesis on the resulting pattern of neuronal connectivity. A mathematical model of neuronal network activity was employed, with plasticity instantiated by an activity-dependent rewiring rule. In particular, the authors modeled a neural system as a collection of "nodes" (neural subsystems) connected by "links" (anatomical connectivity). Neuronal damage was simulated by deletion of nodes in this evolving network through either random or targeted attack. Neurogenesis was likewise simulated by insertion of new nodes with random connections. Local and global structural network properties were characterized using the metrics of local and global "efficiency," and network "reachability." Activity-dependent plasticity yields a network that is robust to random node deletion, with preservation of a "small-world" architecture, characterized by high local and global efficiency. In contrast, targeted deletion of central nodes leads to a drop in reachability and global efficiency, with a consequent loss of small-world properties. Simulated neurogenesis is able to compensate for this targeted cell loss even when rates of new cell formation are considerably slower than that of simulated cell death. The rapid growth of computational neuroscience enables to study the interplay between neuronal plasticity and cell death in computational models of brain network activity. Although the current simulations lack much of the rich physiology of real neuronal systems, they nevertheless allow us to make tentative hypotheses of the effects of neuronal lesions on the resulting neuroanatomical connectivity networks.
| 19,001,355
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Acetylaszonalenin biosynthesis in Neosartorya fischeri. Identification of the biosynthetic gene cluster by genomic mining and functional proof of the genes by biochemical investigation.
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Based on the structural information of acetylaszonalenin isolated from Neosartorya fischeri, a putative biosynthetic gene cluster was identified in the genome sequence of this fungus by genomic mining. This cluster consists of three genes coding for a putative non-ribosomal peptide synthetase (AnaPS), a prenyltransferase (AnaPT), and an acetyltransferase (AnaAT). The coding sequences of anaPT and anaAT were cloned in pQE70 and pQE60, respectively, and overexpressed in Escherichia coli. The soluble His(6) fusion proteins were purified to near homogeneity and characterized biochemically. The structures of the enzymatic products were elucidated by NMR and mass spectroscopy analysis. AnaPT was found to catalyze the reverse prenylation of (R)-benzodiazepinedione at position C3 of the indole moiety in the presence of dimethylallyl diphosphate, resulting in formation of aszonalenin. AnaAT was found to catalyze the acetylation of aszonalenin at position N1 of the indoline moiety in the presence of acetyl coenzyme A, resulting in formation of acetylaszonalenin. Km values of AnaPT were determined for dimethylallyl diphosphate at 156 microm and for (R)-benzodiazepinedione at 232 microm. Km values of AnaAT were determined for acetyl coenzyme A at 96 microm and for aszonalenin at 61 microm. The turnover numbers of the AnaPT and AnaAT reactions were determined at 1.5 and 0.14 s(-1), respectively.
| 19,001,367
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3-mercaptopropionate dioxygenase, a cysteine dioxygenase homologue, catalyzes the initial step of 3-mercaptopropionate catabolism in the 3,3-thiodipropionic acid-degrading bacterium variovorax paradoxus.
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The thioether 3,3-thiodipropionic acid can be used as precursor substrate for biotechnological synthesis of 3-mercaptopropionic acid-containing polythioesters. Therefore, the hitherto unknown catabolism of this compound was elucidated to engineer novel and improved polythioester biosynthesis pathways in the future. Bacteria capable of using 3,3-thiodipropionic acid as the sole source of carbon and energy for growth were enriched from the environment. From eleven isolates, TBEA3, TBEA6, and SFWT were morphologically and physiologically characterized. Their 16 S rDNAs and other features affiliated these isolates to the beta-subgroup of the proteobacteria. Tn5::mob mutagenesis of isolate Variovorax paradoxus TBEA6 yielded ten mutants fully or partially impaired in growth on 3,3-thiodipropionic acid. Genotypic characterization of two 3,3-thiodipropionic acid-negative mutants demonstrated the involvement of a bacterial cysteine dioxygenase (EC 1.13.11.22) homologue in the further catabolism of the 3,3-thiodipropionic acid cleavage product 3-mercaptopropionic acid. Detection of 3-sulfinopropionate in the supernatant of one of these mutants during cultivation on 3,3-thiodipropionic acid as well as in vivo and in vitro enzyme assays using purified protein demonstrated oxygenation of 3-mercaptopropionic acid to 3-sulfinopropionate by this enzyme; cysteine and cysteamine were not used as substrate. Beside cysteine dioxygenase and cysteamine dioxygenase, this 3-mercaptopropionic acid dioxygenase is the third example for a thiol dioxygenase and the first report about the microbial catabolism of 3-mercaptopropionic acid. Insertion of Tn5::mob in a gene putatively coding for a family III acyl-CoA-transferase resulted in the accumulation of 3-sulfinopropionate during cultivation on 3,3-thiodipropionic acid, indicating that this compound is further metabolized to 3-sulfinopropionyl-CoA and subsequently to propionyl-CoA.
| 19,001,372
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The frizzled-related sFRP2 gene is a target of thyroid hormone receptor alpha1 and activates beta-catenin signaling in mouse intestine.
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The thyroid hormone receptor TRalpha1 regulates intestinal development and homeostasis by controlling epithelial proliferation in the crypts. This involves positive control of the Wnt/beta-catenin pathway. To further investigate the effect of thyroid hormone-TRalpha1 signaling on the intestinal epithelium proliferating compartment, we performed a comparative transcription profile analysis on laser microdissected crypt cells recovered from wild type animals with normal or perturbed hormonal status, as well as from TR knock-out mice. Statistical analysis and an in silico approach allowed us to identify 179 differentially regulated genes and to group them into organized functional networks. We focused on the "cell cycle/cell proliferation" network and, in particular, on the Frizzled-related protein sFRP2, whose expression was greatly increased in response to thyroid hormones. In vitro and in vivo analyses showed that the expression of sFRP2 is directly regulated by TRalpha1 and that it activates beta-catenin signaling via Frizzled receptors. Indeed, sFRP2 stabilizes beta-catenin, activates its target genes, and enhances cell proliferation. In conclusion, these new data, in conjunction with our previous results, indicate a complex interplay between TRalpha1 and components of the Wnt/beta-catenin pathway. Moreover, we describe in this study a novel mechanism of action of sFRP2, responsible for the activation of beta-catenin signaling.
| 19,001,373
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Characterization of the differential roles of the twin C1a and C1b domains of protein kinase C-delta.
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Classic and novel protein kinase C (PKC) isozymes contain two zinc finger motifs, designated "C1a" and "C1b" domains, which constitute the recognition modules for the second messenger diacylglycerol (DAG) or the phorbol esters. However, the individual contributions of these tandem C1 domains to PKC function and, reciprocally, the influence of protein context on their function remain uncertain. In the present study, we prepared PKCdelta constructs in which the individual C1a and C1b domains were deleted, swapped, or substituted for one another to explore these issues. As isolated fragments, both the deltaC1a and deltaC1b domains potently bound phorbol esters, but the binding of [(3)H]phorbol 12,13-dibutyrate ([(3)H]PDBu) by the deltaC1a domain depended much more on the presence of phosphatidylserine than did that of the deltaC1b domain. In intact PKCdelta, the deltaC1b domain played the dominant role in [(3)H]PDBu binding, membrane translocation, and down-regulation. A contribution from the deltaC1a domain was nonetheless evident, as shown by retention of [(3)H]PDBu binding at reduced affinity, by increased [(3)H]PDBu affinity upon expression of a second deltaC1a domain substituting for the deltaC1b domain, and by loss of persistent plasma membrane translocation for PKCdelta expressing only the deltaC1b domain, but its contribution was less than predicted from the activity of the isolated domain. Switching the position of the deltaC1b domain to the normal position of the deltaC1a domain (or vice versa) had no apparent effect on the response to phorbol esters, suggesting that the specific position of the C1 domain within PKCdelta was not the primary determinant of its activity.
| 19,001,377
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Agreement rates for sleep/wake judgments obtained via accelerometer and sleep diary: a comparison.
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Agreement rates for waking and sleeping obtained via sleep diary and accelerometer were evaluated, to compare the two methods. Sleep/wake data for consecutive days and nights were surveyed in 119 healthy university students. Accelerometer sleep/wake judgments obeyed the standard algorithm. Agreement rates for waking and sleeping according to accelerometer versus sleep diary, respectively, were calculated. Sleep diary data were set as a baseline. Seventy-six subjects (63.9%), 22 to 32 years of age, presented perfect data for the analysis. The mean sleep times, in minutes, judged by sleep diary and by accelerometer, were 482.3 and 629.6, respectively. The mean percentages and standard deviations of agreement on wake and sleep were 77.5% (SD = 10.2) and 86.1% (SD = 6.2), respectively. There was a significant negative relationship between the agreement rates for wake and sleep (r = -.482, p < .01). The accelerometer showed some measurement failure during waking, presumably because of the decrease in body movement. Sleep diary data during daytime appear to be more valid for detecting a sleep/wake cycle than are accelerometer data. In contrast, nocturnal sleep diary data might be supplemented by the use of an accelerometer as long as participants do not have insomnia.
| 19,001,393
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Taboo, emotionally valenced, and emotionally neutral word norms.
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Although taboo words are used to study emotional memory and attention, no easily accessible normative data are available that compare taboo, emotionally valenced, and emotionally neutral words on the same scales. Frequency, inappropriateness, valence, arousal, and imageability ratings for taboo, emotionally valenced, and emotionally neutral words were made by 78 native-English-speaking college students from a large metropolitan university. The valenced set comprised both positive and negative words, and the emotionally neutral set comprised category-related and category-unrelated words. To account for influences of demand characteristics and personality factors on the ratings, frequency and inappropriateness measures were decomposed into raters' personal reactions to the words versus raters' perceptions of societal reactions to the words (personal use vs. familiarity and offensiveness vs. tabooness, respectively). Although all word sets were rated higher in familiarity and tabooness than in personal use and offensiveness, these differences were most pronounced for the taboo set. In terms of valence, the taboo set was most similar to the negative set, although it yielded higher arousal ratings than did either valenced set. Imageability for the taboo set was comparable to that of both valenced sets. The ratings of each word are presented for all participants as well as for single-sex groups. The inadequacies of the application of normative data to research that uses emotional words and the conceptualization of taboo words as a coherent category are discussed. Materials associated with this article may be accessed at the Psychonomic Society's Archive of Norms, Stimuli, and Data, www.psychonomic.org/archive.
| 19,001,397
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The British Sign Language (BSL) norms for age of acquisition, familiarity, and iconicity.
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Research on signed languages offers the opportunity to address many important questions about language that it may not be possible to address via studies of spoken languages alone. Many such studies, however, are inherently limited, because there exist hardly any norms for lexical variables that have appeared to play important roles in spoken language processing. Here, we present a set of norms for age of acquisition, familiarity, and iconicity for 300 British Sign Language (BSL) signs, as rated by deaf signers, in the hope that they may prove useful to other researchers studying BSL and other signed languages. These norms may be downloaded from www.psychonomic.org/archive.
| 19,001,399
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C-CAT: a computer software used to analyze and select Chinese characters and character components for psychological research.
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The Character-Component Analysis Toolkit (C-CAT) software was designed to assist researchers in constructing experimental materials using traditional Chinese characters. The software package contains two sets of character stocks: one suitable for research using literate adults as subjects and one suitable for research using schoolchildren as subjects. The software can identify linguistic properties, such as the number of strokes contained, the character-component pronunciation regularity, and the arrangement of character components within a character. Moreover, it can compute a character's linguistic frequency, neighborhood size, and phonetic validity with respect to a user-selected character stock. It can also search the selected character stock for similar characters or for character components with user-specified linguistic properties.
| 19,001,401
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Denervation induces cytosolic phospholipase A2-mediated fatty acid hydroperoxide generation by muscle mitochondria.
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Previously, we demonstrated that mitochondria from denervated muscle exhibited dramatically higher Amplex Red dependent fluorescence (thought to be highly specific for hydrogen peroxide) compared with control muscle mitochondria. We now demonstrate that catalase only partially inhibits the Amplex Red signal in mitochondria from denervated muscle. In contrast, ebselen (a glutathione peroxidase mimetic and inhibitor of fatty acid hydroperoxides) significantly inhibits the Amplex Red signal. This suggests that the majority of the Amplex Red signal in mitochondria from denervated muscle is not derived from hydrogen peroxide. Because Amplex Red cannot react with substrates in the lipid environment, we hypothesize that lipid hydroperoxides formed within the mitochondrial lipid bilayer are released as fatty acid hydroperoxides and react with the Amplex Red probe. We also suggest that the release of fatty acid hydroperoxides from denervated muscle mitochondria may be an important determinant of muscle atrophy. In support of this, muscle atrophy and the Amplex Red signal are inhibited in caloric restricted mice and in transgenic mice that overexpress the lipid hydroperoxide-detoxifying enzyme glutathione peroxidase 4. Finally, we propose that cytosolic phospholipase A2 may be a potential source of these hydroperoxides.
| 19,001,413
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Mechanisms associated with tolerance to flooding during germination and early seedling growth in rice (Oryza sativa).
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Flooding slows seed germination, imposes fatalities and delays seedling establishment in direct-seeded rice. This study describes responses of contrasting rice genotypes subjected to flooding or low oxygen stress during germination and discusses the basis of tolerance shown by certain cultivars. In one set of experiments, dry seeds were sown in soil and either watered normally or flooded with 10 cm of water. Seedling survival and shoot and root growth were assessed and seed portions of germinating seedlings were assayed for soluble sugars and starch concentrations. The whole germinating seedlings were assayed for amylase and peroxidase activities and for ethylene production. Activities of enzymes associated with anaerobic respiration were examined and gene expression was analysed separately with seeds germinating under different amounts of dissolved oxygen in dilute agar. Flooding during germination reduced survival but to a lesser extent in tolerant genotypes. Starch concentration in germinating seeds decreased while sugar concentration increased under flooding, but more so in tolerant genotypes. Amylase activity correlated positively with elongation (r = 0.85 for shoot and 0.83 for root length) and with plant survival (r = 0.92). Tolerant genotypes had higher amylase activity and higher RAmy3D gene expression. Ethylene was not detected in seeds within 2 d after sowing, but increased thereafter, with a greater increase in tolerant genotypes starting 3 d after sowing. Peroxidase activity was higher in germinating seeds of sensitive genotypes and correlated negatively with survival. Under low oxygen stress, tolerant genotypes germinate, grow faster and more seedlings survive. They maintain their ability to use stored starch reserves through higher amylase activity and anaerobic respiration, have higher rates of ethylene production and lower peroxidase activity as germinating seeds and as seedlings. Relevance of these traits to tolerance of flooding during germination and early growth is discussed.
| 19,001,425
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Involvement of c-FLIP and survivin down-regulation in flexible heteroarotinoid-induced apoptosis and enhancement of TRAIL-initiated apoptosis in lung cancer cells.
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The flexible heteroarotinoid, SHetA2, is a novel compound with apoptosis-inducing and anticancer activities in vitro and in vivo. Our previous research showed that up-regulation of death receptor 5 plays a critical role in the mechanism of SHetA2-induced apoptosis in human lung cancer cells. The hypothesis of this study was that the mechanism of SHetA2-induced apoptosis requires modulation of additional proteins critical for regulation of apoptosis, including cellular FLICE-inhibitory protein (c-FLIP), survivin, X-linked inhibitor of apoptosis, Bcl-2, Bcl-X(L), Bax, and Bim. Western blot analysis showed that c-FLIP and survivin were substantially reduced in all of the tested cell lines exposed to SHetA2 compared with other proteins that were reduced only in a subset of the cell lines tested. Strikingly, overexpression of c-FLIP, but not survivin, protected cells from SHetA2-induced apoptosis and enhancement of TRAIL-initiated apoptosis, although knockdown of endogenous survivin did slightly sensitize cells to SHetA2-induced apoptosis. Consistent with these results, small interfering RNA-mediated reduction of c-FLIP was more effective than survivin down-regulation in triggering apoptosis in these cell lines. SHetA2 increased ubiquitination of c-FLIP and the consequent degradation was abrogated by the proteasome inhibitor MG132. Although SHetA2 treatment led to increased c-Jun phosphorylation, the JNK inhibitor SP600125 did not prevent c-FLIP down-regulation by SHetA2. Thus, it appears that SHetA2 down-regulates c-FLIP levels by facilitating its ubiquitin/proteasome-mediated degradation independent of JNK activation. Collectively, the present study indicates that, in addition to death receptor 5 up-regulation, c-FLIP down-regulation is another important component of flexible heteroarotinoid (SHetA2)-induced apoptosis as well as enhancement of TRAIL-induced apoptosis.
| 19,001,438
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Psorospermin structural requirements for P-glycoprotein resistance reversal.
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Resistance to chemotherapy reduces its effectiveness, resulting in increased mortality. Psorospermin, a natural product, is a topoisomerase II-directed DNA alkylating agent active against multidrug-resistant (MDR) cell lines, including multiple myeloma. In this study, the mechanism of the P-glycoprotein (P-gp) modulation activity of psorospermin and that of its associated pharmacophore were examined. Flow cytometry shows that doxorubicin-resistant multiple myeloma cells (8226/D40) pretreated with psorospermin enhance intracellular retention of doxorubicin compared with control (75% versus 38%). Because the overexpression of P-gp is the primary cause of drug resistance in the 8226/D40 cells, psorospermin-induced sensitization was likely due to mdr1/P-gp expressional or functional inhibition. As shown by PCR and Western blot, neither transcription of mdr1 nor translation of P-gp was down-regulated by psorospermin treatment. Therefore, the mechanism of psorospermin-induced resistance reversal is most likely through a direct interaction between psorospermin and P-gp. Furthermore, because only the (2'R,3'R) isomer of psorospermin showed any resistance reversal activity, the side chain of psorospermin is apparently a crucial moiety for resistance reversal. By understanding the mechanism of psorospermin-induced MDR modulation, psorospermin and similar compounds can be combined with other chemotherapies to treat resistant cancers.
| 19,001,443
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Surgical repair of coronary sinus atrial septal defect and supraventricular tachycardia.
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A 67-year-old female had suffered from fatigue and palpitation. Cardiac examination revealed coronary sinus atrial septal defect, moderate mitral and tricuspid regurgitation, coronary artery disease, and supraventricular tachycardia with paroxysmal atrial fibrillation. Surgical repair of the anomaly, regurgitant valves, and arrhythmia associated with coronary revascularization was successfully performed and the patient has been doing well in normal sinus rhythm.
| 19,001,454
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ProtorP: a protein-protein interaction analysis server.
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The PROTORP server analyses protein-protein associations in 3D structures. The server calculates a series of physical and chemical parameters of the protein interaction sites that contribute to the binding energy of the association. These parameters include, size and shape, intermolecular bonding, residue and atom composition and secondary structure contributions. The server is flexible, in that it allows users to analyse individual protein associations or large datasets of associations deposited in the PDB, or upload and analyse proprietary files. The properties calculated can be compared with parameter distributions for non-homologous datasets of different classes of protein associations provided on the server website. The server provides an efficient way of characterizing protein-protein associations of new or existing proteins, and a means of putting these values in the context of previously observed associations. http://www.bioinformatics.sussex.ac.uk/protorp
| 19,001,476
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Memory and attention problems in children with chronic fatigue syndrome or myalgic encephalopathy.
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To understand more about the problems children with chronic fatigue syndrome (CFS) or myalgic encephalopathy (ME) experience with memory and attention, and to test the feasibility of quantitative measurement of both memory and attention. Four-item semistructured questionnaire and neuropsychological test battery with 10 psychometric subtests. Family home of the child taking part. 20 children with a diagnosis of CFS/ME experiencing memory and/or concentration problems were recruited between April and October 2007 from a regional CFS/ME clinical service (female 13; average age 13.5 years; range 8-16). Each child, parent and teacher was asked to describe the child's memory and attention problems. Responses were subject to thematic analysis by two independent researchers. In addition, each child completed a battery of 10 tests to measure: processing speed; attention; immediate and delayed memory; working memory; executive function. Raw scores were converted into age-scaled scores and the children's psychometric scores on the 10 tests taken were compared with normative data using t tests. Children with CFS/ME, their parents and teachers described problems with focussed attention, sustained attention, recall and stress. Scores for sustained attention (mean 8.1, 95% CI 6.3 to 9.9), switching attention (7.5, 5.5 to 9.4), divided attention (6.9, 5.5 to 8.2), auditory learning (8.2, 6.8 to 9.6) and immediate recall (8.7, 7.3 to 10.0) appeared lower than the normative mean of 10. Children with CFS/ME appear to experience problems with attention, which may have adverse implications for verbal memory. These cognitive problems may explain some of the educational difficulties associated with CFS.
| 19,001,478
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Effects of nigral stimulation on locomotion and postural stability in patients with Parkinson's disease.
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The physiopathology of gait and balance disorders in Parkinson's disease patients is still poorly understood. Levodopa treatment and subthalamic nucleus (STN) stimulation improve step length and walking speed, with less effect on postural instability. These disorders have been linked to dysfunction of the descending basal ganglia outputs to brainstem structures. In this study, we evaluated the effects of stimulation of the substantia nigra pars reticulata (SNr), on locomotion and balance in Parkinson's disease patients. Biomechanical parameters and leg muscle activity were recorded during gait initiation in seven selected patients operated for bilateral STN stimulation, out of 204 stimulated patients, with one contact of each electrode located within the SNr. Step length, anteroposterior and vertical velocities of the centre of gravity were studied, with special reference to the subjects' ability to brake the centre of gravity fall before foot-contact, and compared to seven controls. In Parkinson's disease patients, five treatment conditions were tested: (i) no treatment, (ii) levodopa treatment, (iii) STN stimulation, (iv) SNr stimulation and (v) combined levodopa treatment and STN stimulation. The effects of these treatments on motor parkinsonian disability were assessed with the UPDRS III scale, separated into 'axial' (rising from chair, posture, postural stability and gait) and 'distal' scores. Whereas levodopa and/or STN stimulation improved 'axial' and 'distal' motor symptoms, SNr stimulation improved only the 'axial' symptoms. Compared to controls, untreated Parkinson's disease patients showed reduced step length and velocity, and poor braking just prior to foot-contact, with a decrease in both soleus (S) and anterior tibialis (AT) muscle activity. Step length and velocity significantly increased with levodopa treatment alone or in combination with STN stimulation in both natural and fast gait conditions, and with STN stimulation alone in the fast gait condition. Conversely, SNr stimulation had no significant effect on these measures in either condition. In the natural gait condition, no fall in the centre of gravity occurred as step length was low and active braking was unnecessary. In the fast gait condition, braking was improved with STN or SNr stimulation but not with levodopa treatment, with an increase in the stance leg S muscle activity. These results suggest that anteroposterior (length and velocity) and vertical (braking capacity) gait parameters are controlled by two distinct systems within the basal ganglia circuitry, representing respectively locomotion and balance. The SNr, a major basal ganglia output known to project to pontomesencephalic structures, is postulated as being particularly involved in balance control during gait.
| 19,001,482
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uPAR-deficient mouse keratinocytes fail to produce EGFR-dependent laminin-5, affecting migration in vivo and in vitro.
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The urokinase receptor (uPAR) is involved in a series of pathological processes, from inflammation to cancer. We have analyzed in detail the role of uPAR and the mechanisms involved in keratinocyte behavior during wound healing by exploiting uPAR-knockout (KO) mice. In vivo, uPAR-KO mice showed delayed wound healing, with abnormal keratinocyte migration and proliferation. In vitro, unlike wild-type cells, primary uPAR-KO keratinocytes did not proliferate in response to epidermal growth factor (EGF), their growth and migration were not inhibited by EGF-receptor (EGFR) inhibitors, and they did not adhere to uncoated surfaces. Whereas EGFR levels in uPAR-KO keratinocytes were normal, there was no tyrosine phosphorylation upon addition of EGF, and its downstream targets, extracellular-signal-regulated kinases 1 and 2 (ERK1/2), were not activated. Re-introduction of mouse uPAR rescued all phenotypes. In vitro adhesion and migration defects were associated with the failure of uPAR-KO keratinocytes to normally produce and secrete laminin-5 (LN5), an event that requires EGFR signaling. These results were confirmed in vivo, with LN5 being upregulated during wound healing in wild-type but not in uPAR-KO epidermis.
| 19,001,498
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The leukemogenic t(8;21) fusion protein AML1-ETO controls rRNA genes and associates with nucleolar-organizing regions at mitotic chromosomes.
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RUNX1/AML1 is required for definitive hematopoiesis and is frequently targeted by chromosomal translocations in acute myeloid leukemia (AML). The t(8;21)-related AML1-ETO fusion protein blocks differentiation of myeloid progenitors. Here, we show by immunofluorescence microscopy that during interphase, endogenous AML1-ETO localizes to nuclear microenvironments distinct from those containing native RUNX1/AML1 protein. At mitosis, we clearly detect binding of AML1-ETO to nucleolar-organizing regions in AML-derived Kasumi-1 cells and binding of RUNX1/AML1 to the same regions in Jurkat cells. Both RUNX1/AML1 and AML1-ETO occupy ribosomal DNA repeats during interphase, as well as interact with the endogenous RNA Pol I transcription factor UBF1. Promoter cytosine methylation analysis indicates that RUNX1/AML1 binds to rDNA repeats that are more highly CpG methylated than those bound by AML1-ETO. Downregulation by RNA interference reveals that RUNX1/AML1 negatively regulates rDNA transcription, whereas AML1-ETO is a positive regulator in Kasumi-1 cells. Taken together, our findings identify a novel role for the leukemia-related AML1-ETO protein in epigenetic control of cell growth through upregulation of ribosomal gene transcription mediated by RNA Pol I, consistent with the hyper-proliferative phenotype of myeloid cells in AML patients.
| 19,001,502
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Differential effects of octreotide and pasireotide on somatostatin receptor internalization and trafficking in vitro.
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The clinically used somatostatin analogs, octreotide and lanreotide, act primarily by binding to somatostatin receptor 2 (sst2). In contrast, the novel multireceptor ligand pasireotide (SOM230) binds with high affinity to somatostatin receptor subtypes sst1, sst2, sst3, and sst5. SOM230 is currently under clinical evaluation for treatment of acromegaly, Cushing's disease, and octreotide-resistant carcinoid tumors. However, the effects of SOM230 on internalization and postendosomal sorting of individual human somatostatin receptor subtypes have not been determined so far. Here we show that SOM230 was less potent than octreotide in inducing internalization and signaling of sst2 receptors expressed in human embryonic kidney cells. In contrast, SOM230 was more potent than octreotide in inducing internalization and signaling of sst3 and sst5 receptors. Both SOM230 and octreotide stimulated a rapid down-regulation of sst3 but not of sst2 or sst5 receptors. SOM230 and octreotide profoundly differed in their patterns of sst2-stimulated beta-arrestin mobilization. Whereas octreotide-mediated receptor activation led to the formation of stable complexes facilitating the internalization of sst2 and beta-arrestin-2 into the same endocytic vesicles, SOM230-mediated receptor activation led to the formation of unstable complexes that dissociated at or near the plasma membrane. Consequently, sst2 receptors recycled rapidly to the plasma membrane after endocytosis in SOM230-treated cells, but not in octreotide-treated cells. We show that SOM230 modulates somatostatin receptor trafficking in a manner clearly distinct from octreotide and somatostatin. These findings may provide an explanation for the differential regulation of somatostatin receptor responsiveness during long-term administration of stable somatostatin analogs.
| 19,001,514
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Impact of somatostatin analogs versus surgery on glucose metabolism in acromegaly: results of a 5-year observational, open, prospective study.
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The aim of the study was to investigate the 5-yr impact of surgery and somatostatin analogs (SSA) on glucose metabolism in acromegaly. We conducted an observational, prospective, comparative, nonrandomized study. The 100 patients (48 women, 52 men; median age, 49 yr) in the study were grouped as follows for treatment: SSA only (group A; n = 34); SSA followed by surgery (group B; n = 20); surgery only (group C; n = 30); and surgery followed by SSA (group D; n = 16). At diagnosis, 28% had impaired glucose tolerance, and 22% had diabetes mellitus; fasting glucose levels (4.13-10.60 mmol/liter) were best predicted by age (t = 2.88; P = 0.0049) and disease duration (t = 1.99; P = 0.049). After 60 months, fasting glucose levels reduced (-4.9 +/- 19.7%) in group A only, whereas they did not change in the other groups. In the 68 nondiabetic patients at baseline, fasting glucose levels increased by 0.7 +/- 11.2%, 7.5 +/- 10.3%, 4.3 +/- 10.4%, and 4.3 +/- 14.8% (P = 0.28), from groups A to D, respectively. Percentage change of fasting glucose in all patients receiving SSA was 1.9 +/- 12.3%, and in those not receiving SSA it was 6.4 +/- 10.8% (P = 0.13). Overall, prevalence of new onset of diabetes during SSA treatment was nine of 55 (16.4%) vs. three of 23 after surgery (13.0%, P = 0.98). Deterioration of glucose tolerance was correlated with increased body mass index (r = 0.49, P < 0.0001) and not with use of SSA or surgery (r = 0.06; P = 0.53), control or not of GH (r = -0.10, P = 0.31) and IGF-I (r = -0.12; P = 0.22). The results of this study demonstrate a similar deterioration of glucose tolerance after 60 months in patients receiving SSA or cured with surgery. Increase in body mass index was the major predictor of deterioration of glucose tolerance.
| 19,001,517
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Pharmaceutical care for migraine and headache patients: a community-based, randomized intervention.
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Despite the high prevalence of headache and migraine in the general population, many people do not receive adequate medical attention and treatment. To evaluate the effects of pharmaceutical care (defined as intensified structured counseling between patient and pharmacist, including the use of drug databases), for patients with headache or migraine, on both clinical and psychological endpoints. A prospective, randomized, controlled intervention study was conducted using pharmacies in Northern Germany. A total of 112 pharmacies (26% of all pharmacies in the study region) recruited 410 patients with headaches. Pharmacies were randomly assigned to an intervention or control group. Patients were interviewed by telephone prior to the intervention and again after 4 months. Primary endpoints were number of days with headache, number and severity of headaches, self-efficacy, and the patients' perceptions of their health-related quality of life. Each pharmacy treated an average of 4.6 patients (total time effort 9 h). The intervention group consisted of 201 patients who received pharmaceutical care, whereas the control group comprised 209 patients who received standard counseling. In both groups, the number of headache attacks and intensity of pain in treated headache attacks did not change significantly between the first and second interviews. However, a statistically significant improvement in mental health and self-efficacy was shown in the intervention group. Intensity of pain in untreated headache attacks and the number of days with headache decreased in both groups. Most participants described this intervention as helpful and effective and 90% reported that they would recommend pharmaceutical care to other patients with headache. A short-term pharmaceutical care intervention improved patients' mental health and self-efficacy, although it did not significantly change the number and severity of headaches. The increase in self-efficacy and mental health associated with pharmaceutical care may be instrumental in improving long-term pharmacotherapy of patients with migraine and headache. To fully assess the effects of pharmaceutical care, a longer study may be required.
| 19,001,531
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Temporal and spatial development of axonal maturation and myelination of white matter in the developing brain.
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Diffusion tensor imaging (DTI) has been widely used to investigate the development of white matter (WM). However, information about this development in healthy children younger than 2 years of age is lacking, and most previous studies have only measured fractional anisotropy (FA). This study used FA and radial and axonal diffusivities in children younger than 2 years of age, aiming to determine the temporal and spatial development of axonal maturation and myelination of WM in healthy children. A total of 60 healthy pediatric subjects were imaged by using a 3T MR imaging scanner. They were divided into 3 groups: 20 at 3 weeks, 20 at 1 year of age, and 20 at 2 years of age. All subjects were imaged asleep without sedation. FA and axial and radial diffusivities were obtained. Eight regions of interest were defined, including both central and peripheral WM for measuring diffusion parameters. A significant elevation in FA (P < .0001) and a reduction in axial and radial diffusivities (P < .0001) were observed from 22 days to 1 year of age, whereas only radial diffusivity showed significant changes (P = .0014) from 1 to 2 years of age. The region-of-interest analysis revealed that FA alone may not depict the underlying biologic underpinnings of WM development, whereas directional diffusivities provide more insights into the development of WM. Finally, the spatial development of WM begins from the central to the peripheral WM and from the occipital to the frontal lobes. With both FA and directional diffusivities, our results demonstrate the temporal and spatial development of WM in healthy children younger than 2 years of age.
| 19,001,533
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Variability of homotopic and heterotopic callosal connectivity in partial agenesis of the corpus callosum: a 3T diffusion tensor imaging and Q-ball tractography study.
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Little is known about the anatomic connectivity of callosal axons in individuals with partial agenesis of the corpus callosum (pAgCC). We used tractography based on both diffusion tensor imaging (DTI) and high angular resolution diffusion imaging (HARDI) to investigate interhemispheric white matter connectivity in pAgCC. DTI and HARDI were performed at 3T on 6 individuals with pAgCC and 8 control subjects. For HARDI analysis, a Q-ball reconstruction method capable of visualizing multiple intravoxel fiber orientations was used. In both DTI and HARDI, whole-brain 3D fiber tractography was performed by using deterministic streamline algorithms. Callosal fibers were then segmented to identify separately connections between homologous cortical regions (homotopic fibers) and nonhomologous regions (heterotopic fibers) by using manually drawn regions of interest. In control individuals, we observed densely connected homotopic fibers. However, in individuals with pAgCC, we identified not only homotopic connections but also heterotopic connections in 4 of 6 subjects. Furthermore, the observed homotopic connections in pAgCC did not necessarily correlate with the position or size of the residual callosum. The nature of homotopic and heterotopic connectivity varied considerably among subjects with pAgCC, and HARDI recovered more callosal fibers than DTI. Individuals with pAgCC demonstrate a remarkable diversity of callosal connectivity, including a number of heterotopic tracts that are absent in healthy subjects. The patterns of their callosal connections cannot be predicted from the appearance of their callosal fragments on conventional MR imaging. More tracts and more extensive fibers within tracts are recovered with HARDI than with DTI.
| 19,001,538
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Management and control of hypertension and proteinuria in patients with advanced chronic kidney disease under nephrologist care or not: data from the AVENIR study (AVantagE de la Nephroprotection dans l'Insuffisance Renale).
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Little is known about antihypertensive management and control of blood pressure (BP) and proteinuria in patients with chronic kidney disease (CKD). Data from a large observational study (AVENIR), carried out in Lorraine (France), were used to analyse antihypertensive treatment and control of BP and proteinuria in patients with advanced CKD, under nephrologist care or not. All adults with CKD, beginning dialysis in 2005 and 2006, were included and categorized into patients 'under nephrologist care' and 'not under nephrologist care' at the time when treatment, BP and proteinuria results were considered. All data were collected retrospectively from medical records. Demographic and clinical data were from initiation of dialysis. BP, biological and therapeutic data were results obtained at 2.7 months before dialysis for patients under nephrologist care, and results obtained at the first nephrology consultation for those not under such care (2.7 +/- 3.7 months before dialysis). On 566 included patients, the 291 under nephrologist care received more antihypertensive agents (3.1 +/- 1.5 versus 2.2 +/- 1.6) than the 275 not under such care and each antihypertensive class was more often prescribed for these patients, particularly the renin-angiotensin-aldosteron system inhibitors (60.5% versus 36.7%). Nevertheless, BP did not differ between both groups, and proteinuria control was achieved in more patients not under nephrologist care, revealing a likely bias of indication. Whatever the type of care, BP < 130/80 mmHg was achieved in only one quarter of all patients and proteinuria < 0.5 g/day in only 15% of them. Understanding the reasons for such a poor level of hypertension and proteinuria control in CKD patients needs to be explored in further investigations.
| 19,001,561
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Expression of H(+),K(+)-ATPase and glycopattern analysis in the gastric glands of Rana esculenta.
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A multidisciplinary study involving lectin histochemistry, IHC, immuno-lectin blotting, and immunogold was carried out to determine the distribution of sugar residues in the glycoproteins of Rana esculenta oxynticopeptic cells. We considered animals in two experimental conditions, fasting and fed. It is known that, in mammals, the tubulovesicular membranes are rich in proteins with several functions. The proton pump H(+),K(+)-ATPase, a heterodimeric complex with a catalytic alpha-subunit and a heavily glycosylated beta-subunit, responsible for acid secretion, is the most abundant. No data have been published regarding the localization and the structures of H(+),K(+)-ATPase in amphibians. In the water frog, the luminal membrane and tubulovesicular system of oxynticopeptic cells, which differ in morphology according to their functional stage, reacted with the primary gold-conjugated antibody against the H(+),K(+)-ATPase alpha-subunit. By lectin histochemistry and immunoblotting, in the oxynticopeptic cells of R. esculenta we detected the presence of N-linked glycans having fucosylated (poly)lactosamine chains, which could correspond to the oligosaccharide chains of the beta subunit. The latter are somewhat different from those described in mammals, and this is probably because of an adaptation to the different microenvironmental conditions in which the oxynticopeptic cells find themselves, in terms of their different habits and phylogeny.
| 19,001,639
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Placenta accreta: spectrum of US and MR imaging findings.
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Placenta accreta (PA) encompasses various types of abnormal placentation in which chorionic villi attach directly to or invade the myometrium. PA is a significant cause of maternal morbidity and mortality and is now the most common reason for emergent postpartum hysterectomy. Its prevalence has risen tenfold in the United States over the past 50 years, primarily due to the increasing percentage of pregnant patients undergoing primary and repeat cesarean sections. Placenta previa and previous cesarean section are the two most important known risk factors for PA. Accurate prenatal identification of affected pregnancies allows optimal obstetric management. Ultrasonography (US) remains the diagnostic standard, and routine US examination at 18-20 weeks gestation affords an ideal opportunity to screen for the disorder. Placental lacunae and abnormal color Doppler imaging patterns are the most helpful US markers for PA. In recent years, there has been increased interest in magnetic resonance (MR) imaging for the evaluation of PA, since it can provide information on depth of invasion and more clearly depict posterior placentas. The most reliable MR imaging findings are uterine bulging, heterogeneous placenta, and placental bands. Focal interruptions in the hypointense myometrial border may also be helpful. PA is a clinical and diagnostic challenge that is being encountered with increasing frequency. Clinicians should be aware of the clinical issues, risk factors, and imaging findings associated with PA to facilitate optimal case management.
| 19,001,647
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Pediatric MR cholangiopancreatography: principles, technique, and clinical applications.
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High-quality magnetic resonance (MR) cholangiopancreatographic images are difficult to obtain in children due to the small caliber of the pediatric bile ducts and to motion artifacts. However, there has been ongoing improvement in image quality, thanks to better coil technology, increased speed of acquisition, refinement in respiratory compensation techniques, and newer sequences. Heavily T2-weighted fast spin-echo (FSE) and single-shot FSE MR imaging sequences with long echo times are used to image the biliary and pancreatic ducts. Secretin has been shown to improve the visualization of the pancreatic duct and pancreaticobiliary junction. Factors that affect image quality in pediatric MR cholangiopancreatography include sedation, negative oral contrast material, radiofrequency coil selection, respiratory compensation techniques, echo time, echo train length, section-slab thickness, planes of scanning, field of view, and number of signals acquired. However, giving proper attention to these factors and tailoring the study to the body size of the patient (which varies considerably) can lead to high-quality diagnostic MR cholangiopancreatographic images. Use of MR cholangiopancreatography in children is limited by the need for sedation or anesthesia, high cost, limited availability, and long scanning times. Nonetheless, this modality can be a viable alternative to endoscopic retrograde cholangiopancreatography (ERCP) in the evaluation of various entities such as choledochal cyst, recurrent pancreatitis, primary sclerosing cholangitis, and a transplanted liver, and may obviate ERCP.
| 19,001,651
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Flat-panel volume CT: fundamental principles, technology, and applications.
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Flat-panel volume computed tomography (CT) systems have an innovative design that allows coverage of a large volume per rotation, fluoroscopic and dynamic imaging, and high spatial resolution that permits visualization of complex human anatomy such as fine temporal bone structures and trabecular bone architecture. In simple terms, flat-panel volume CT scanners can be thought of as conventional multidetector CT scanners in which the detector rows have been replaced by an area detector. The flat-panel detector has wide z-axis coverage that enables imaging of entire organs in one axial acquisition. Its fluoroscopic and angiographic capabilities are useful for intraoperative and vascular applications. Furthermore, the high-volume coverage and continuous rotation of the detector may enable depiction of dynamic processes such as coronary blood flow and whole-brain perfusion. Other applications in which flat-panel volume CT may play a role include small-animal imaging, nondestructive testing in animal survival surgeries, and tissue-engineering experiments. Such versatility has led some to predict that flat-panel volume CT will gain importance in interventional and intraoperative applications, especially in specialties such as cardiac imaging, interventional neuroradiology, orthopedics, and otolaryngology. However, the contrast resolution of flat-panel volume CT is slightly inferior to that of multidetector CT, a higher radiation dose is needed to achieve a comparable signal-to-noise ratio, and a slower scintillator results in a longer scanning time.
| 19,001,655
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From the archives of the AFIP: central nervous system infections associated with human immunodeficiency virus infection: radiologic-pathologic correlation.
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Diseases of the central nervous system (CNS) in patients infected with the human immunodeficiency virus (HIV) result directly from HIV itself or from a variety of opportunistic agents. These infections include progressive multifocal leukoencephalopathy, toxoplasmosis, and cryptococcosis. A resurgence of tuberculosis and neurosyphilis has also been documented. Mass lesions, meningoencephalitis, demyelination, atrophy, and vascular lesions are the commonly encountered imaging findings. The introduction of highly active antiretroviral therapy (HAART) has improved both the clinical and radiologic findings in HIV-infected patients and reduced the number of opportunistic infections. In countries that use HAART, AIDS (acquired immunodeficiency syndrome) dementia complex is becoming the most common neurologic complication of HIV infection, whereas opportunistic infections are still the major cause of neurologic complications in patients from countries that do not commonly use HAART. Immune reconstitution inflammatory syndrome, which occurs in some patients in the weeks to months after the institution of HAART, may alter the typical imaging appearance of infectious diseases involving the CNS. Knowledge of the spectrum of imaging findings of these infectious diseases, as well as the effect that treatment has on imaging appearances, is important in the evaluation of HIV-infected patients.
| 19,001,657
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Cripto localizes Nodal at the limiting membrane of early endosomes.
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Cripto is a glycosylphosphatidylinositol (GPI)-anchored co-receptor of Nodal and several other transforming growth factor-beta (TGF-beta) family ligands. It contains an epidermal growth factor (EGF)-like motif and a Cripto-FRL1-Cryptic (CFC) domain, which are conserved in a family of EGF-CFC proteins. The EGF domain is thought to recruit Nodal, whereas the CFC domain mediates binding to activin receptor-like kinase 4 (ALK4). We found that the EGF-like motif of Cripto was not essential for its binding to Nodal. However, through residues phenylalanine 78 and glycine 71, Cripto enriched Nodal at the limiting membrane of early endosomes. Similarly, residues in the CFC domain that mediate binding of Cripto to ALK4 were required to attenuate sequestration of Nodal in the endosomal lumen. Thus, we propose that Cripto stimulates Nodal activity by localizing it at the interface of endosomes with cytoplasmic effectors. To our knowledge, Cripto is the first GPI-anchored protein shown to control intraendosomal sorting of its associated cargo.
| 19,001,664
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Effect of dietary monosodium glutamate on trans fat-induced nonalcoholic fatty liver disease.
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The effects of dietary monosodium glutamate (MSG) on trans-fatty acid (TFA)-induced nonalcoholic fatty liver disease (NAFLD) are addressed in an animal model. We used Affymetrix microarray analysis to investigate hepatic gene expression and the contribution of visceral white adipose tissue (WAT) to diet-induced NAFLD. Trans-fat feeding increased serum leptin, FFA, HDL-cholesterol (HDL-C), and total cholesterol (T-CHOL) levels, while robustly elevating the expression of genes involved in hepatic lipogenesis, including the transcription factor sterol-regulatory element binding protein 1c. Histological examination revealed hepatic macrosteatosis in TFA-fed animals. Conversely, dietary MSG at doses similar to human average daily intake caused hepatic microsteatosis and the expression of beta-oxidative genes. Serum triglyceride, FFA, and insulin levels were elevated in MSG-treated animals. The abdominal cavities of TFA- or MSG-treated animals had increased WAT deposition compared with controls. Microarray analysis of WAT gene expression revealed increased lipid biosynthetic gene expression, together with a 50% decrease in the key transcription factor Ppargc1a. A combination of TFA+MSG resulted in the highest levels of serum HDL-C, T-CHOL, and leptin. Microarray analysis of TFA+MSG-treated livers showed elevated expression of markers of hepatic inflammation, lipid storage, cell damage, and cell cycle impairment. TFA+MSG mice also had a high degree of WAT deposition and lipogenic gene expression. Levels of Ppargc1a were further reduced to 25% by TFA+MSG treatment. MSG exacerbates TFA-induced NAFLD.
| 19,001,666
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Assessment of dosimetrical performance in 11 Varian a-Si-500 electronic portal imaging devices.
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Dosimetrical characteristics of 11 Varian a-Si-500 electronic portal imaging devices (EPIDs) in clinical use for periods ranging between 10 and 86 months were investigated for consistency of performance and portal dosimetry implications. Properties studied include short-term reproducibility, signal linearity with monitor units, response to reference beam, signal uniformity across the detector panel, signal dependence on field size, dose-rate influence, memory effects and image profiles as a function of monitor units. The EPID measurements were also compared with those of the ionization chambers' to ensure stability of the linear accelerators. Depending on their clinical installation date, the EPIDs were interfaced with one of the two different acquisition control software packages, IAS2/IDU-II or IAS3/IDU-20. Both the EPID age and image acquisition system influenced the dosimetric characteristics with the newer version (IAS3 with IDU-20) giving better data reproducibility and linearity fit than the older version (IAS2 with IDU-II). The relative signal response (uniformity) after 50 MU was better than 95% of the central value and independent of detector. Sensitivity for all EPIDs reduced continuously with increasing dose rates for the newer image acquisition software. In the dose-rate range 100-600 MU min(-1), the maximum variation in sensitivity ranged between 1 and 1.8% for different EPIDs. For memory effects, the increase in the measured signal at the centre of the irradiated field for successive images was within 1.8% and 1.0% for the older and newer acquisition systems, respectively. Image profiles acquired at a lower MU in the radial plane (gun-target) had gradients in measured pixel values of up to 25% for the older system. Detectors with software/hardware versions IAS3/IDU-20 have a high degree of accuracy and are more suitable for routine quantitative IMRT dosimetrical verification.
| 19,001,691
|
Multi-ray-based system matrix generation for 3D PET reconstruction.
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Iterative image reconstruction algorithms for positron emission tomography (PET) require a sophisticated system matrix (model) of the scanner. Our aim is to set up such a model offline for the YAP-(S)PET II small animal imaging tomograph in order to use it subsequently with standard ML-EM (maximum-likelihood expectation maximization) and OSEM (ordered subset expectation maximization) for fully three-dimensional image reconstruction. In general, the system model can be obtained analytically, via measurements or via Monte Carlo simulations. In this paper, we present the multi-ray method, which can be considered as a hybrid method to set up the system model offline. It incorporates accurate analytical (geometric) considerations as well as crystal depth and crystal scatter effects. At the same time, it has the potential to model seamlessly other physical aspects such as the positron range. The proposed method is based on multiple rays which are traced from/to the detector crystals through the image volume. Such a ray-tracing approach itself is not new; however, we derive a novel mathematical formulation of the approach and investigate the positioning of the integration (ray-end) points. First, we study single system matrix entries and show that the positioning and weighting of the ray-end points according to Gaussian integration give better results compared to equally spaced integration points (trapezoidal integration), especially if only a small number of integration points (rays) are used. Additionally, we show that, for a given variance of the single matrix entries, the number of rays (events) required to calculate the whole matrix is a factor of 20 larger when using a pure Monte-Carlo-based method. Finally, we analyse the quality of the model by reconstructing phantom data from the YAP-(S)PET II scanner.
| 19,001,696
|
[Effect of fructose-1,6-diphosphete on myocardial preservation during pulmonary operations].
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To investigate the effect of fructose-1,6-diphosphete(FDP) on myocardial preservation in pulmonary operations. One hundred and six patients undergoing selective pulmonary lobectomy or segmentectomy were randomly divided into 2 groups with 53 patients each. FDP 200 mg/kg was infused intravenously before anesthesia in the FDP group, while 5% glucose with the same volume was given instead of FDP in the control group. ECGs were monitored from before the anesthesia to 72 h after the operation;the time and type of arrhythmia were recorded. Blood samples were taken before the operation (T0), immediately after the operation(T1), at 24 h(T2),48 h(T3)and 72 h(T(4)) after the operation to determine plasma creatine kinase isoenzyme MB(CK-MB) and cardiac troponin I(cTnI) concentrations. The incidence of arrhythmia in FDP group (35 times) was significantly lower than that in the control group(67 times). The incidence of all types of arrhythmia in the FDP group was also significantly lower than that in the control group. The concentrations of CK-MB and cTnI in the FDP group were significantly lower than those in the control group at T1, T2, T3, and T4. FDP is effective for myocardial preservation in pulmonary operations.
| 19,001,742
|
Vitamin A intake is inversely related with adiposity in healthy young adults.
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Dietary intake, either through specific nutrients or representative food groups, can influence obesity-related oxidative stress markers. This study evaluated the potential associations between vitamin A intake and several anthropometrical, biochemical and dietary features in healthy young adults, emphasizing the putative relationships between total antioxidant consumption and vitamin A intake. This translational research enrolled 61 healthy young adults aged 18-22 y. Anthropometrical and blood pressure measurements, blood samples and nutritional intake data were collected. After adjusting for total energy intake, vitamin A intake showed a negative correlation with several adiposity measurements. Furthermore, vitamin A consumption was positively associated with serum total cholesterol as well as with the intake of antioxidant foodstuffs. So, vitamin A intake seems to be related, not only with the total antioxidant intake, but also with several anthropometrical and biochemical measurements linked to metabolic syndrome manifestations and other features related to oxidative stress in healthy young adults.
| 19,001,764
|
Sequence diversity of the Bla g 4 cockroach allergen, homologous to lipocalins, from Blattella germanica.
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The cockroach allergen Bla g 4, a putative lipocalin, is known to exhibit frequent sequence variations. However, the previously reported cDNA sequences are truncated at the N terminus. This study was undertaken to investigate the mechanisms by which these sequence variations are generated. Rapid amplification of cDNA ends PCR and RT-PCR were performed to obtain the full sequence of the Bla g 4 cDNA, and PCR was also used to clone the Bla g 4 genomic DNA. In addition, Bla g 4 protein variants were analyzed by two-dimensional gel electrophoresis. Nine additional amino acid residues at the N terminus of Bla g 4 were identified, and 2 genes encoding Bla g 4, both of which consisted of 5 exons, were cloned. Examination of 34 clones of Bla g 4 cDNA obtained by RT-PCR revealed 14 variants. In particular, Bla g 4 sequences showed frequent clusters of variations in residues 38-45, 61-82 and 144-163. Differences in cDNA sequences may imply that RNA sequences are edited after transcription. More than 10 spots were identified between pH 5 and 7 upon two-dimensional gel electrophoresis, indicating that multiple variants of Bla g 4 are produced at the protein level. Genetic polymorphisms among individual cockroaches, the existence of multiple genes and sequence variations caused by RNA editing produce sequence diversity of Bla g 4, which may influence its allergenicity. The sequence information obtained in this study will be helpful for the standardization of the cockroach allergen and thereby aid in the development of diagnostics and immunotherapeutics.
| 19,001,794
|
Porphyria cutanea tarda, hepatitis C, uroporphyrinogen decarboxylase and mutations of HFE gene. A case-control study.
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Hemochromatosis gene (HFE) mutations and the hepatitis C virus (HCV) are known risk factors for porphyria cutanea tarda (PCT), but interactions with erythrocytic uroporphyrinogen decarboxylase (UROD) have seldom been addressed. In order to examine the links between these factors, we conducted a multicentre prospective case-control study. PCT patients with (n = 32) or without HCV (n = 28) were matched to HCV+ (n = 32) and HCV- controls (n = 28). HFE mutations (C282Y and H63D) were analyzed by PCR. PCT+/HCV+ patients were younger than PCT+/HCV- patients (46.9 vs. 58.2 years, p < 0.001). UROD values were not significantly different in HCV+ and HCV- patients. Both C282Y and H63D were more frequent in PCT+ patients than in controls, but there was no difference in HFE genotype according to HCV seropositivity. Mean UROD was lower in case of HFE mutations in both PCT patients and controls. In French patients, HCV infection is probably the major causal factor of PCT. It is not linked with HFE mutations, although they are significantly associated with PCT. A low erythrocytic UROD might be a predisposing factor. The UROD value was lower in patients with HFE mutations, suggesting a possible interaction between HFE genotype and UROD levels.
| 19,001,803
|
Lifestyle drugs in old age--a mini-review.
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Normal aging is no disease. The individual lifestyle may be responsible for a large fraction of the so-called 'age-related' changes. An increasing number of healthy individuals make use of 'lifestyle' drugs, such as nootropics, psychopharmaca, hormones and ecodrugs. In this respect, the fact that many people try to improve their outer appearance, to solve their 'cosmetic problems', to influence their rate of hair growth and to altogether delay, halt or even reverse the natural aging process has become a relevant matter for the practising doctor. Lifestyle drugs are taken in an attempt to increase personal life quality by means of attaining a certain psychosocially defined medical or beauty ideal, rather than to manage a medically identifiable, well-defined disease. Often, patients suffering from somatoform disorders such as hypochondriac disorders, body dysmorphic disorders, somatization disorders or persistent somatoform pain disorders may spontaneously ask physicians to prescribe them lifestyle drugs. Also, when 'healthy' people demand a lifestyle drug, possible side effects and contraindications must be taken into consideration and ruled out.
| 19,001,804
|
Posttransplant immunosuppression in highly sensitized patients.
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Recent desensitization protocols using the combination of plasmapheresis (PP) or immunoadsorption to remove donor-specific anti-HLA antibodies (DSA) and/or intravenous immunoglobulin (IVIG) and rituximab to downregulate antibody-mediated immune responses have made kidney transplantation feasible by abrogating cross-match positivity. Despite good short-term patient and graft survival, acute antibody-mediated rejection (AMR) continued to be an important barrier seen in 20-30% of patients receiving desensitization protocols and it is still not clear which protocol (high-dose IVIG, PP/low-dose IVIG), what type of induction treatment (thymoglobulin, anti-IL-2R antibodies, alemtuzumab), or addition of rituximab is better for the prevention of early acute AMR. Future prospective, multicenter, and randomized trials are required to decide the ideal protocol for sensitized patients.
| 19,001,811
|
[The gap between research and practice--a survey among participants in continuing medical education events].
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To investigate to which extent physicians participating in specialization and continuing medical education courses read clinical research articles and how relevant they deem this for their practical work. Physicians participating in courses on homeopathy (n = 96), acupuncture (n = 79), naturopathy (n = 75), family medicine (n = 50) and internal medicine (n = 136) filled in a questionnaire. They were asked to what extent and how they kept themselves informed about clinical research, how their daily work was affected by clinical research and why they did not spend more time reading clinical research literature. More than half of the participants (51%) reported they did not spend any time reading original research articles. Differences between the five groups of physicians were small. The proportion of physicians who considered the relevance of clinical trials for practical work as high or very high was 52% among participants of courses on homeopathy, 68% on acupuncture, 67% on naturopathy, 63% on family medicine and 81% in the internal medicine event. In all groups of physicians the relevance of clinical trials and meta-analyses to daily work was rated lower than that of personal experience, advice from colleagues, continuing medical education events, pathophysiological explanations, textbooks and guidelines. The large amount of time required to read original articles was reported as a major reason for the limited interest in clinical research. Among the physicians participating in this survey clinical trials and meta-analyses were only of subordinate relevance for clinical decision making.
| 19,001,823
|
Natural host relationships and genetic diversity of rodent-associated hantaviruses in southeastern Brazil.
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Hantaviruses are rodent-borne RNA viruses that have caused hantavirus cardiopulmonary syndrome in several Brazilian regions. In the present study, geographical distribution, seroprevalence, natural host range, and phylogenetic relations of rodent-associated hantaviruses collected from seven counties of Southeastern Brazil were evaluated. ELISA, RT-PCR and phylogenetic analysis were used in this study. Antibodies to hantavirus were detected in Bolomys lasiurus, Akodon sp. and Oligoryzomys sp., performing an overall seroprevalence of 5.17%. All seropositive rodents were associated with grasslands or woods surrounded by sugar cane fields. Phylogenetic analysis of partial S- and M-segment sequences showed that viral sequences isolated from B. lasiurus specimens clustered with Araraquara virus. However, a sequence from Akodon sp. shared 100% similarity with Argentinian/Chilean viruses based on the partial S-segment amino acid sequence. These results indicate that there are associations between rodent reservoirs and hantaviruses in some regions of Southeastern Brazil, and suggest the existence of additional hantavirus genetic diversity and host ecology in these areas.
| 19,001,829
|
Phosphate binder impact on bone remodeling and coronary calcification--results from the BRiC study.
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Calcium-containing phosphate binders have been shown to increase the progression of vascular calcification in hemodialysis patients. This is a prospective study that compares the effects of calcium acetate and sevelamer on coronary calcification (CAC) and bone histology. 101 hemodialysis patients were randomized for each phosphate binder and submitted to multislice coronary tomographies and bone biopsies at entry and 12 months. The 71 patients who concluded the study had similar baseline characteristics. On follow-up, the sevelamer group had higher levels of intact parathyroid hormone (498 +/- 352 vs. 326 +/- 236 pg/ml, p = 0.017), bone alkaline phosphatase (38 +/- 24 vs. 28 +/- 15 U/l, p = 0.03) and deoxypyridinoline (135 +/- 107 vs. 89 +/- 71 nmol/l, p = 0.03) and lower LDL cholesterol (74 +/- 21 vs. 91 +/- 28 mg/dl, p = 0.015). Phosphorus (5.8 +/- 1.0 vs. 6 +/- 1.0 mg/dl, p = 0.47) and calcium (1.27 +/- 0.07 vs. 1.23 +/- 0.08 mmol/l, p = 0.68) levels did not differ between groups. CAC progression (35 vs. 24%, p = 0.94) and bone histological diagnosis at baseline and 12 months were similar in both groups. Patients of the sevelamer group with a high turnover at baseline had an increase in bone resorption (eroded surface, ES/BS = 9.0 +/- 5.9 vs. 13.1 +/- 9.5%, p = 0.05), whereas patients of both groups with low turnover at baseline had an improvement in bone formation rate (BFR/BS = 0.015 +/- 0.016 vs. 0.062 +/- 0.078, p = 0.003 for calcium and 0.017 +/- 0.016 vs. 0.071 +/- 0.084 microm(3)/microm(2)/day, p = 0.010 for sevelamer). There was no difference in CAC progression or changes in bone remodeling between the calcium and the sevelamer groups.
| 19,001,830
|
[Private or public dental care? Patients' perception and experience in Lithuania].
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To compare demographic and social groups of patients, their satisfaction with services in public and private dental institutions. A random sample of 3000 Lithuanian residents was selected; 1801 participants answered a postal questionnaire. The response rate was 60.0%. Univariate analysis, chi(2) criterion, z-test, and multiple logistic regression were used to evaluate the association between institution type, demographic and social characteristics of the respondents. RESULTS. Less than half of Lithuanian residents (41.2%) visited public dental institutions, 35.9%--private, 25.9%--both. They preferred private dental sector due to better quality of service, public--due to closeness to residence or being the treatment place of acquaintances. Patients visiting public institutions required cheaper treatment, while patients visiting private institutions--qualitative, though more expensive, using modern technologies. The number of dental visits in the past year was lower in public institutions than in private ones. The majority of patients treated in public, private, and both institutions were satisfied with dental services. The least satisfied were visiting both institutions. More respondents with secondary and lower education used public services as compared to those with higher education. Urban population visited public institutions more often than rural population. Respondents with a monthly income of less than 500 Lt for one family member used public dental services more often than those receiving a higher income. Older patients visited public dental institutions more often than younger ones. CONCLUSIONS. More Lithuanian residents are treated in public dental institutions (up to 67.1%) than in private. Older, receiving lower income patients preferred public institutions. The majority of patients in public clinics as well as in private sector are satisfied with the service. Those who visited both types of institutions were least satisfied with dental services.
| 19,001,839
|
Influence of laser-welding and electroerosion on passive fit of implant-supported prosthesis.
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This study investigated the influence of laser welding and electroerosion procedure on the passive fit of interim fixed implant-supported titanium frameworks. Twenty frameworks were made from a master model, with five parallel placed implants in the inter foramen region, and cast in commercially pure titanium. The frameworks were divided into 4 groups: 10 samples were tested before (G1) and after (G2) electroerosion application; and another 10 were sectioned into five pieces and laser welded before (G3) and after (G4) electroerosion application. The passive fit between the UCLA abutment of the framework and the implant was evaluated using an optical microscope Olympus STM (Olympus Optical Co., Tokyo, Japan) with 0.0005mm of accuracy. Statistical analyses showed significant differences between G1 and G2, G1 and G3, G1 and G4, G2 and G4. However, no statistical difference was observed when comparing G2 and G3. These results indicate that frameworks may show a more precise adaptation if they are sectioned and laser welded. In the same way, electroerosion improves the precision in the framework adaptation.
| 19,001,843
|
The orthodontic treatment in Lithuania: accessibility survey.
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The objective of the present study was to assess the public accessibility of orthodontic care in Lithuania. In 2008, a request for the information about various aspects of public orthodontic care during 2000-2007 in Lithuania was submitted to the State Patients' Fund at the Ministry of Health. The data on the demographic distribution of orthodontists in Lithuania were received from the Lithuanian Dental Chamber. The authors of the paper also analyzed the national legislation regulating the State Patients' Fund expenditure on orthodontic care and treatment. In 2007, there were 73 orthodontists-practitioners in Lithuania, most of them highly concentrated in major cities and towns: most of them were practicing in Vilnius (22) and Kaunas (20), while there were only 5 orthodontists in Klaipeda, 4 in Siauliai, 3 in each of Panevezys and Marijampole. The public orthodontic treatment is rendered only to patients suffering from most severe pathologies. With the constantly increasing expenditure of the State Patients' Fund, the national public orthodontic care system definitely undergoes significant development: the number of patients who received the treatment with removable and with fixed orthodontic appliances was gradually increasing during 2002-2007, with however, a very small number of new facilities for ambulatory treatment facilities of orthodontists (consultations included). The number of patients who received treatment with removable orthodontic appliances was specifically higher in Siauliai and Telsiai, Panevezys and Utena districts, with fixed orthodontic appliances - in Vilnius and Alytus, Kaunas and Marijampole, Panevezys and Utena regions. The analysis of the availability of public orthodontic treatment showed a marked increase in the number highly-specialized ambulatory facilities in Vilnius and Alytus district in 2002-2007. Specialists providing orthodontic treatment in the country are highly concentrated, while in general public orthodontic treatment undergoes development at the moment. The accessibility of orthodontic treatment in Lithuania, especially in the regions distant from Vilnius and Kaunas, remains inadequate.
| 19,001,845
|
Specialization of the general transcriptional machinery in male germ cells.
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In adult animals, spermatogenesis involves a continuous differentiation of the spermatogonial stem and progenitor cell population into mature sperm. A unique aspect of this developmental process is the germ cell-specific expression and function of paralogues of components of the general transcription machinery, notably subunits of TFIID. Genetic and biochemical studies show that these paralogues play critical, but mechanistically distinct roles in Drosophila and mouse spermatogenesis.
| 19,001,848
|
ATMINistrating ATM signalling: regulation of ATM by ATMIN.
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The checkpoint kinase ATM (ataxia telangiectasia mutated) transduces genomic stress signals to halt cell cycle progression and promote DNA repair in response to DNA damage. We have recently identified an essential cofactor for ATM, ATMIN (for ATM INteractor). Several observations suggested that ATMIN plays a key role in ATM signalling. ATMIN and ATM protein stability were mutually dependent, which indicated an intimate physical and functional interaction. ATMIN bound ATM using a short carboxy-terminal motif, in a manner analogous to how another ATM cofactor, Nijmegen Breakage Syndrome protein 1 (NBS1), associates with ATM. ATMIN and NBS1 had complementary functions in ATM signalling. ATMIN was required for ATM signalling by chloroquine and hypotonic stress, but not after induction of double-stand breaks by ionizing radiation (IR), whereas NBS1 is required for ATM signalling by IR. This suggested competition of NBS1 and ATMIN for ATM binding in a signal-dependent fashion. Some implications of these findings for the ATM signalling pathway are discussed.
| 19,001,856
|
mTOR regulates autophagy-associated genes downstream of p73.
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The p53 family consists of three transcription factors, p53, p63 and p73 that share domain architecture and sequence identity. The mTOR (mammalian target of rapamycin) kinase responds to growth factors and nutrient levels to regulate cellular growth and autophagy. Whereas p53 acts both upstream and downstream of mTOR, gene signature-based analyses have revealed that p73 is inhibited by mTOR activity. p53 can both activate and repress autophagy levels depending on cellular context. While less is known about p73, recent studies have shown that it induces cellular autophagy and multiple autophagy-associated genes downstream of mTOR. Chromatin immunoprecipitation analyses demonstrate that endogenous p73 binds the regulatory regions of genes such as ATG5, ATG7 and UVRAG. How p73 regulates the expression levels of these genes in response to different cellular stresses remains unknown. Because p53 family members play key roles in tumor suppression, development, aging and neurodegeneration, the context and manner by which these transcription factors regulate autophagy may have implications for a wide range of human diseases.
| 19,001,857
|
NFBD1/MDC1, 53BP1 and BRCA1 have both redundant and unique roles in the ATM pathway.
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NFBD1/MDC1, 53BP1 and BRCA1 are DNA damage checkpoint proteins with twin BRCT domains. In order to determine if they have redundant roles in responses to ionizing radiation, we used siRNA and shRNA to deplete NFBD1, 53BP1 and BRCA1 in single, double and triple combinations. These analyses were performed in early passage human foreskin fibroblasts so that checkpoint responses could be assessed in a normal genetic background. We report that NFBD1, 53BP1 and BRCA1 have both unique and redundant functions in radiation-induced phosphorylation and localization events in the ATM-Chk2 pathway. 53BP1, but not NFBD1 and BRCA1, mediates ionizing radiation-induced ATM S1981 autophosphorylation. In contrast, all three mediators collaborate to promote IR-induced Chk2 T68 phosphorylation. NFBD1 and 53BP1, but not BRCA1, work together to mediate pATMS1981, pChk2T68 and NBS1 ionizing radiation induced foci (IRIF). However, the relative importance of NFBD1 and 53BP1 in IRIF formation differ. We also determined the interdependence among mediators in IRIF recruitment. We extend previous findings in cancer cells and mouse cells that NFBD1 is upstream of 53BP1 and BRCA1 to primary human cells. Furthermore, NFBD1 promotes BRCA1 IRIF through both 53BP1-dependent and 53BP1-independent mechanisms.
| 19,001,859
|
Potential role of lysosomal dysfunction in the pathogenesis of primary open angle glaucoma.
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Primary open angle glaucoma (POAG) is a late onset disease usually accompanied by elevated intraocular pressure (IOP) that results from the failure of the trabecular meshwork (TM) to maintain normal levels of aqueous humor outflow resistance. Cells in the TM are subjected to chronic oxidative stress through reactive oxygen species (ROS) present in the aqueous humor (AH) and generated by normal metabolism. Exposure to ROS is thought to contribute to the morphological and physiological alterations of the outflow pathway in aging and POAG. Our results indicate that chronic exposure of TM cells to oxidative stress causes the accumulation of nondegradable material within the lysosomal compartment leading to diminished lysosomal activity and increased SA-beta-Gal expression. Because the lysosomal compartment is responsible for maintaining general cellular turnover, such impaired activity may lead to a progressive cellular decline in the TM cell function and thus contribute to the progression of POAG.
| 19,001,861
|
Cleavage of MCM2 licensing protein fosters senescence in human keratinocytes.
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In eukaryotic cells, MCM, the minichromosome maintenance proteins, form a heterohexamer during G(1) phase in the cell cycle and constitute a DNA helicase activity at the onset of replication. MCM proteins are downregulated and dissociated from chromatin when cells exit the cell cycle. MCM proteins are upregulated frequently in a variety of dysplastic and cancer cells. To delineate the role of MCM in esophageal epithelial biology, we determined the MCM family gene expression during cellular senescence, immortalization, differentiation and apoptosis. All of the MCM2-7 proteins appeared to be downregulated in primary human esophageal keratinocytes upon replicative senescence. Their expression was restored by ectopic expression of a catalytic subunit of human telomerase, resulting in immortalization. Interestingly, we found a reciprocal induction of a novel MCM2-related protein fragment upon cell growth inhibition associated with senescence, contact inhibition or terminal differentiation, but not apoptosis. Epitope mapping of this MCM2-related fragment suggested the lack of amino- and carboxyl-terminal regions, including one of the putative nuclear localization signals and the ATPase domain, the MCM box. The absence of multiple MCM2 transcripts implied a possible posttranslational molecular cleavage in generation of the MCM2-related fragment, and a potential functional role in the regulation of the activity of the MCM protein complex.
| 19,001,876
|
Cardiovascular aging and exercise in healthy older adults.
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Physical inactivity in an aging population is a major contributing factor to the rising numbers of older persons with chronic illnesses and disabilities. The purpose of this article is to review the relationship between physical inactivity and age-associated changes to the cardiovascular system, and provide guidance on prescribing exercise to healthy older persons in order to mitigate the adverse effects of cardiovascular aging. Interpretive review of the literature. A number of structural and functional changes occur in the cardiovascular system with advancing age, many of which are mediated by changes in vascular stiffness. These changes lead not only to cardiovascular events and strokes, but also to frailty, functional decline, and cognitive impairment. A substantial proportion of the decline in aerobic capacity with age may result from physical inactivity. Guidelines for the prescription of aerobic, resistance, and balance training for otherwise healthy older persons are provided. Lack of physical activity is a major risk factor for the epidemic of chronic disease and disability facing an aging population. Many age-associated changes in cardiovascular function result from physical inactivity. The benefits of regular exercise include prevention of cardiovascular events, disability, and cognitive impairment. Age is not a contraindication to exercise, which can usually be initiated safely in older persons.
| 19,001,881
|
Ionizing radiation and risk of laryngeal cancer among German uranium miners.
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Today it is uncontested that uranium miners are at increased risk of lung cancer, primarily owing to their exposure to radon. Whether they are also at an increased risk of cancer at other sites, especially in the respiratory tract, remains under discussion. The aim of the present study was to examine the laryngeal cancer risk among uranium miners. An individually matched case-control study of former uranium miners in East Germany was conducted, including 554 cases and 929 controls. Using conditional logistic regression models, a dose-response relationship between the risk of developing a laryngeal cancer and exposure to radon progeny could not be confirmed. Even in miners with a cumulative exposure of at least 1,000 WLM, only a slightly elevated risk could be observed of OR = 1.13 (0.75-1.70)95%. The study does not support the hypothesis of an association between exposure to short-lived radon progeny and laryngeal cancer risk. Moreover, signs are emerging that smoking could explain the moderate excess in laryngeal cancer cases observed in some miner cohorts.
| 19,001,899
|
Radiological concerns in operation of intense low-energy deuteron beams.
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A 40-keV, 5-mA DC deuteron beam was operated at the SARAF with the purpose of characterizing the ion source and the low-energy beam transport system. We used this opportunity to address radiological concern of operating an intense deuteron beam. Fast and thermal neutrons produced via the D(d,n) reaction were measured in the vicinity of the components intercepting the beam using various methods. We found that the neutron yield from implantation of a deuteron beam in a graphite matrix is of the order of 2 x 10(6) n s(-1) mA(-1) into 4pi.
| 19,001,902
|
Family caregiver support and hospitalizations of patients with heart failure.
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This study aimed to expand understanding of hospitalizations involving patients with heart failure by considering characteristics of the caregiver as a facet of the problem. In face-to-face interviews, 41 caregivers registered agreement or disagreement on a Likert scale of items associated with caregiver depressive symptoms, caregiver appraisal, and perceptions of patient disease severity. Correlation and regression analyses showed lack of family support, increased care hours at home, and greater perceived patient disease severity to be associated with higher rates of hospitalizations for patients with heart failure.
| 19,001,918
|
Clinical value of echocardiographic assessment of coronary flow reserve after left anterior descending coronary artery stenting in an unselected population.
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Transthoracic Doppler echocardiography is a valuable tool to measure coronary flow reserve (CFR) and detect in-stent restenosis (ISR) after percutaneous coronary angioplasty in selected series of patients. To assess the usefulness of coronary flow reserve measured by echocardiography in detecting significant (> or =70%) ISR of the left anterior descending coronary artery in a large unselected population. Two hundred and twenty-three patients (age 61 +/- 10 years; 168 men) treated with left anterior descending stenting underwent CFR measurement by transthoracic Doppler echocardiography and venous adenosine infusion 24-72 h before control coronary angiography. Coronary-active drugs were continued, and patients with multiple risk factors and old anterior-apical myocardial infarction were included. Significant ISR occurred in 56 patients (25%). Patients with ISR had higher basal coronary flow velocity (27 +/- 10 cm/s vs. 24 +/- 7 cm/s; P < 0.002) and lower CFR (1.5 +/- 0.5 vs. 2.7 +/- 0.6; P < 0.0001) than those without ISR. A linear relation was found between ISR and CFR (r = -0.73; P < 0.0001) and remained significant after adjustment for blood pressure and heart rate (r = -0.74; P < 0.0001). A CFR less than two identified significant ISR (sensitivity 88%, specificity 88%, area under the curve = 0.943; P < 0.001). In a multivariate model of CFR prediction, myocardial infarction and heart rate were slightly contributory (ss = -0.19, P < 0.01; ss = -0.16, P < 0.03, respectively), whereas ISR had a large influence (ss = -0.66; P < 0.0001). The inverse correlation between ISR and CFR persisted in patients with myocardial infarction (r = -0.64; P < 0.0001) and in those treated with beta-blockers (r = -0. 71; P < 0.0001). Echocardiographic measurement of CFR detects significant left anterior descending ISR in unselected patients with multiple risk factors, old anterior-apical myocardial infarction, and taking beta-blockers.
| 19,001,933
|
Extrusion of the device: a rare complication of the pacemaker implantation.
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Skin erosion caused by the pacemaker is widely documented, but the complete extrusion of the device is very rare. We describe the case of a 54-year-old woman who was admitted to hospital because of skin erosion, followed by the complete extrusion of the pacemaker pulse generator out of the subcutaneous pocket. The patient underwent a lead extraction procedure and a new pacemaker, in the contralateral side, was implanted. This case demonstrates that the early stages of skin erosion favoured by the device, if neglected, may cause more serious complications that may require the removal of the hardware.
| 19,001,937
|
Effect of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibition on serum matrix metalloproteinase-13 and tissue inhibitor matrix metalloproteinase-1 levels as a sign of plaque stabilization.
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Atherosclerotic plaques are composed of a lipid rich core, which is covered by a collagen rich fibrous cap. Rupture of the atherosclerotic plaque with superimposed thrombosis is the main cause of acute coronary syndromes, including acute myocardial infarction and unstable angina. The stability of the plaque depends on its collagen content; degradation of the collagen leads to a vulnerable plaque that is prone to rupture. Recent studies have demonstrated a critical role for matrix metalloproteinases (MMPs) in the degradation of the collagen content and the reduction of mechanical stability of the atherosclerotic plaques. Increased expression of various MMPs has been shown in the tissue sections of atherosclerotic plaques. The increased expression of MMPs in the atheroma also leads to increased MMP levels in the circulation. The cholesterol lowering drugs - 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) - decrease the tissue expression of various MMPs in atheromatous plaques by attenuating the inflammatory process that promotes MMP expression during the course of atherosclerosis. However, the effect of statin treatment on the serum levels of MMP-13, which has a critical role in the initiation of collagen degradation, is unknown. On the basis of these previous studies, we discuss the need for studies on the effect of statin treatment on the serum levels of MMP-13 and tissue inhibitor of matrix metalloproteinase (TIMP-1) levels in hypercholesterolemic patients.
| 19,001,938
|
Controlled exposure to combined particles and ozone decreases heart rate variability.
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This experiment was designed to test if controlled exposure to particles and ozone would result in decreased heart rate variability (HRV). Five asthmatic adults were exposed for 4 hours to; filtered-air, carbon and ammonium nitrate particles, and particles and ozone. Twenty-minute electrocardiograms were obtained before and after each exposure. Standard deviation of all normal-to-normal beat intervals (SDNN) decreased significantly across particles and ozone exposure compared with across filtered-air exposure (P = 0.01). Changes in SDNN-I (P = 0.04) and normalized low and high frequency (P = 0.02) were also seen across particles and ozone exposure; although these changes may best be characterized as trends given the small sample size. No significant changes in HRV were seen across the filtered-air or particles-only exposures. The results of this study suggest that combined particle and ozone exposure may decrease HRV in asthmatics. Further investigation is needed to confirm this finding.
| 19,001,951
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A clustering of injury behaviors.
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Alcohol is a well-known risk factor for injury. A number of other behaviors are also associated with injury risk. We hypothesized that risky drinking would be associated with other high risk behaviors, thereby delineating a need for behavioral interventions in addition to alcohol. A consecutive sample of trauma patients was interviewed for drinking and risky behaviors including seat belt use, helmet use, and driving behaviors. The Alcohol Use Disorders Identification Test was used to screen for risky drinking and risky behavior questions were taken from validated questionnaires. Behaviors were ranked on a Likert scale ranging from a low to a high likelihood of the behavior or assessed the frequency of behavior in the past 30 days. An Alcohol Use Disorders Identification Test score of 8 or more was considered risky drinking for adults age 21 to 64, and 4 or more for ages 16 to 20 and over 65. Risky and nonrisky drinkers were compared on behavior risk items. A p value of less than 0.05 was considered significant. One hundred sixty patients (mean age, 36.8 years, 72% men,) were interviewed. Risky drinkers were more likely to drive after consuming alcohol, ride with drinking drivers, tailgate, weave in and out of traffic, and make angry gestures at other drivers (all p < 0.05). Risky drinkers were less likely to wear motorcycle helmets. However, risky drinkers were no more or less likely to talk on the cell phone while driving, to use seatbelts, or use turn signals. Although number of lifetime vehicle crashes were similar, risky drinkers were more likely to have been the party at fault for the crash (mean 1.09 vs. 0.64, p = 0.03). Factors other than alcohol increase injury risk in problem drinkers. Injury prevention programs performing alcohol interventions should consider including behavioral interventions along with alcohol reduction strategies. New screening and intervention programs should be developed for injury behaviors that increase risk but are not alcohol related.
| 19,001,964
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Preinjury beta blockers are associated with increased mortality in geriatric trauma patients.
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Beta-blockade decreases mortality and morbidity in selected older patient populations undergoing noncardiac general surgery. We hypothesized that preinjury beta blockade would increase mortality in geriatric trauma patients, given beta-blockers inhibit patient's physiologic responses to hypovolemic shock. Patients older than 65 years admitted to a level I trauma center were identified by the trauma registry. Medical records were reviewed for demographic and injury information. Preinjury beta blockade was determined by review of nurse and pharmacy admission histories. Logistic regression was used to determine whether there was any correlation between mortality and the use of preinjury beta blockers. Separate models were developed based on the presence or the absence of head injury. Of the 1,598 patients older than 65 years admitted between 1996 and 2006, 1,479 met inclusion criteria. Primary reason for exclusion was lack of documentation. Two hundred seventy-three patients were taking beta blockers before their trauma, and 14.7% died before discharge. Mortality in patients not taking beta blockers was 13.4%. Mortality in patients with head injury was 25.9%, significantly associated with warfarin use (OR 2.5, 95% CI 1.3-4.8). In patients without head injury, preinjury beta blockade had a significant association with mortality (OR 2.1, 95% CI 1.1-4.3). Many factors associated with mortality in elderly trauma patients are similar to the younger patient population. Unique to this population are increased comorbidities and use of prescription medications. Beta blockers, one of these common medications, are associated with increased mortality in the elderly.
| 19,001,968
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Early venous thromboembolism prophylaxis with enoxaparin in patients with blunt traumatic brain injury.
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To determine the safety of early enoxaparin for venous thromboembolism (VTE) prophylaxis in patients with blunt traumatic brain injury (TBI). Prospective observational study of patients with TBI who received enoxaparin within 48 hours after admission. Brain computed tomography (CT) scans were obtained at the time of admission, at 24 hours, and at variable intervals thereafter based on clinical course. Patients were excluded from the study for intracerebral contusions >/=2 cm, multiple contusions within one brain region, subdural or epidural hematomas >/=8 mm, increased size or number of lesions on follow-up CT, persistent intracranial pressure >20 mm Hg, or neurosurgeon or trauma surgeon reluctance to initiate early pharmacologic VTE prophylaxis. Bleeding complications were defined as CT progression of hemorrhage by Marshall CT Classification or radiologists' report, regardless of any neurologic deterioration. Main outcomes measured were intracranial bleeding complications, discharge Glasgow Outcome Score, and hospital mortality. Five hundred twenty-five patients were studied. Eighteen patients (3.4%) had progressive hemorrhagic CT changes after receiving enoxaparin, 12 of whom had no change in treatment, neurologic status, or outcome. Six patients (1.1%) had a change in treatment or potential outcome, including three who required subsequent craniotomy. Twenty-one patients (4.0%) died, and pharmacologic prophylaxis may have contributed to one death (0.2%). Discharge Glasgow Outcome Scores were 445 (84.8%) good recovery, 19 (3.6%) moderate disability, 36 (6.8%) severe disability, 4 (0.8%) persistent vegetative state, and 21 (4.0%) dead. Enoxaparin should be considered as an option for early VTE prophylaxis in selected patients with blunt TBI. Early enoxaparin should be strongly considered in those patients with TBI with additional high risk traumatic injuries.
| 19,001,969
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Percutaneous fluoroscopically guided jejunostomy placement.
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To describe our experience with fluoroscopically guided direct jejunostomy placement in patients with enterocutaneous fistula, or neoplastic or postsurgical changes of the stomach or duodenum that preclude traditional gastrostomy placement. Nineteen patients underwent percutaneous direct jejunostomy tube placement with fluoroscopic guidance from August 2004 through March 2006. There were 15 men and four women whose ages ranged from 28 to 82 years (mean, 54 years). Seven patients had surgical changes to the stomach that precluded traditional gastrostomy access, one patient had a duodenal tumor, two had unresectable gastric tumors, and nine had small bowel pathology that required distal access. Jejunal access was initially successful in 18 of 19 (95%) procedures. Follow-up ranged from 10 days to 509 days. Two catheters were removed as they were no longer needed. Seven patients' initial tubes were still functioning at the end of their follow-up. One tube was removed secondary to pain and irritation at the insertion site. Three tubes were occluded. One patients' tube was inadvertently pulled out. In two patients, feeding was not tolerated secondary to fistula distal to the jejunostomy. Two patients died with their initial tubes. Primary patency was 285 days (95% CI 162-407). One death occurred 10 days postprocedure for a 30-day mortality of 1 of 19 (5%). Percutaneous direct jejunostomy placement is a relatively safe and effective means of gaining enteral access in patients who have enterocutaneous fistula or who have either postsurgical or neoplastic changes of the stomach that preclude traditional gastrostomy placement.
| 19,001,975
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