spalde-v3-lexical
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0.025073638185858727} | 24512064 | Apart from HIV two exogenous retroviruses (human T cell leukaemia viruses type I (HTLV-I) and type II (HTLV-II)) infect humans. HTLV-I infection is endemic in Japan, the Caribbean, Africa, and Melanesia and is found among immigrants from these regions in Europe. HTLV-I infection is associated with a 1-5% lifetime risk of adult T cell leukaemia/lymphoma, 1 a 0.25% lifetime risk of HTLV-I associated myelopathy, 2 and other inflammatory conditions (uveitis, alveolitis, and arthritis).1 HTLV-II infection is endemic in some native American and African peoples and among injecting drug users and has been associated with neurological disease.1 Between 1986 and 1992, 100 cases of HTLV-I associated myelopathy and 44 cases of adult T cell leukaemia/lymphoma were diagnosed in the United Kingdom.3 Adult T cell leukaemia/lymphoma was first described in 1977 and patients with it have a mean life expectancy of only six months, so most of the 44 cases were probably incident cases. … | HTLV-I/II associated disease in England and Wales, 1993-7: retrospective review of serology requests. |
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0.08782484382390976, "27080": 0.5197699069976807, "27559": 0.11343330889940262, "27605": 0.4891071021556854, "27843": 0.9333322048187256, "28024": 0.04207121208310127, "28086": 0.3163207769393921, "28405": 0.272677481174469, "28522": 0.8022117614746094, "28788": 0.17020416259765625, "28797": 0.00875066313892603, "28901": 0.16690383851528168, "29105": 0.15526613593101501, "29107": 0.08064348995685577, "29206": 0.9515975713729858, "29280": 0.3012613356113434, "29290": 0.6704301834106445} | 24512417 | Induced pluripotent stem cells (iPSCs) can be derived from somatic cells by gene transfer of reprogramming transcription factors. Expression levels of these factors strongly influence the overall efficacy to form iPSC colonies, but additional contribution of stochastic cell-intrinsic factors has been proposed. Here, we present engineered color-coded lentiviral vectors in which codon-optimized reprogramming factors are co-expressed by a strong retroviral promoter that is rapidly silenced in iPSC, and imaged the conversion of fibroblasts to iPSC. We combined fluorescence microscopy with long-term single cell tracking, and used live-cell imaging to analyze the emergence and composition of early iPSC clusters. Applying our engineered lentiviral vectors, we demonstrate that vector silencing typically occurs prior to or simultaneously with the induction of an Oct4-EGFP pluripotency marker. Around 7 days post-transduction (pt), a subfraction of cells in clonal colonies expressed Oct4-EGFP and rapidly expanded. Cell tracking of single cell-derived iPSC colonies supported the concept that stochastic epigenetic changes are necessary for reprogramming. We also found that iPSC colonies may emerge as a genetic mosaic originating from different clusters. Improved vector design with continuous cell tracking thus creates a powerful system to explore the subtle dynamics of biological processes such as early reprogramming events. | Lentiviral vector design and imaging approaches to visualize the early stages of cellular reprogramming. |
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0.8649974465370178, "25972": 0.24018502235412598, "26244": 1.1319060325622559, "26305": 0.3676496744155884, "26328": 0.3416208028793335, "26601": 0.040196798741817474, "26741": 0.11168810725212097, "26774": 0.022212404757738113, "26874": 0.603290855884552, "27032": 0.07250232994556427, "27384": 0.2763880789279938, "27480": 0.3269403576850891, "27515": 0.14349138736724854, "27642": 0.304147332906723, "27815": 0.7426811456680298, "28106": 0.0058422754518687725, "28290": 1.1671710014343262, "28393": 0.055094651877880096, "28466": 0.603290855884552, "28685": 0.24631060659885406, "28774": 0.2852376699447632, "28828": 0.7047978043556213, "29101": 0.06612417846918106, "29160": 0.32553088665008545, "29243": 0.757441520690918, "29282": 0.06246116757392883, "29431": 0.05139094591140747, "29461": 0.2830325961112976} | 24521894 | Wolcott-Rallison syndrome (WRS) is a rare, autosomal recessive disorder characterized by permanent neonatal or early infancy insulin-dependent diabetes. Epiphyseal dysplasia, osteoporosis and growth retardation occur at a later age. Other frequent multisystemic manifestations include hepatic and renal dysfunction, mental retardation and cardiovascular abnormalities. On the basis of two consanguineous families, we mapped WRS to a region of less than 3 cM on chromosome 2p12, with maximal evidence of linkage and homozygosity at 4 microsatellite markers within an interval of approximately 1 cM. The gene encoding the eukaryotic translation initiation factor 2-α kinase 3 (EIF2AK3) resides in this interval; thus we explored it as a candidate. We identified distinct mutations of EIF2AK3 that segregated with the disorder in each of the families. The first mutation produces a truncated protein in which the entire catalytic domain is missing. The other changes an amino acid, located in the catalytic domain of the protein, that is highly conserved among kinases from the same subfamily. Our results provide evidence for the role of EIF2AK3 in WRS. The identification of this gene may provide insight into the understanding of the more common forms of diabetes and other pathologic manifestations of WRS. | EIF2AK3, encoding translation initiation factor 2-α kinase 3, is mutated in patients with Wolcott-Rallison syndrome |
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However, little is known about the role of postcentral cortical areas in motor maintenance and their patterns of interaction with motor cortex. We investigated the functional relations of beta-synchronized neuronal assemblies in pre- and postcentral areas of two monkeys as they pressed a hand lever during the wait period of a visual discrimination task. By using power and coherence spectral analysis, we identified a beta-synchronized large-scale network linking pre- and postcentral areas. We then used Granger causality spectra to measure directional influences among recording sites. In both monkeys, strong Granger causal influences were observed from primary somatosensory cortex to both motor cortex and inferior posterior parietal cortex, with the latter area also exerting Granger causal influences on motor cortex. Granger causal influences from motor cortex to postcentral sites, however, were weak in one monkey and not observed in the other. These results are the first, to our knowledge, to demonstrate in awake monkeys that synchronized beta oscillations bind multiple sensorimotor areas into a large-scale network during motor maintenance behavior and carry Granger causal influences from primary somatosensory and inferior posterior parietal cortices to motor cortex. | Beta oscillations in a large-scale sensorimotor cortical network: directional influences revealed by Granger causality. |
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0.0770333781838417, "29461": 0.10203468054533005, "29494": 0.32553088665008545} | 24524403 | The concept of frailty as a medically distinct syndrome has evolved based on the clinical experience of geriatricians and is clinically well recognizable. Frailty is a nonspecific state of vulnerability, which reflects multisystem physiological change. These changes underlying frailty do not always achieve disease status, so some people, usually very elderly, are frail without a specific life threatening illness. Current thinking is that not only physical but also psychological, cognitive and social factors contribute to this syndrome and need to be taken into account in its definition and treatment. Together, these signs and symptoms seem to reflect a reduced functional reserve and consequent decrease in adaptation (resilience) to any sort of stressor and perhaps even in the absence of extrinsic stressors. The overall consequence is that frail elderly are at higher risk for accelerated physical and cognitive decline, disability and death. All these characteristics associated with frailty can easily be applied to the definition and characterization of the aging process per se and there is little consensus in the literature concerning the physiological/biological pathways associated with or determining frailty. It is probably true to say that a consensus view would implicate heightened chronic systemic inflammation as a major contributor to frailty. This review will focus on the relationship between aging, frailty and age-related diseases, and will highlight possible interventions to reduce the occurrence and effects of frailty in elderly people. | Aging, frailty and age-related diseases |
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Most paraquat intoxications happen through oral administration. We report a case of death after intravenous paraquat injection. There is little clinical data on parenteral paraquat exposure, and we describe this case and fatal progression. Toxic symptoms and severe organ function impairment developed soon after injection. Treatment with repeated activated charcoal hemoperfusion with pulse steroids, cyclophosphamide, and antioxidants was attempted. The patient died from multiple organ failure 3 days after intoxication. This case indicates that paraquat intoxication via intravenous injection, even in very small amounts, has an extremely poor prognosis. | A case of paraquat intoxication caused by intravenous injection. |
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"27642": 0.6338034868240356, "27710": 1.1128336191177368, "27833": 0.11081436276435852, "28024": 0.17840765416622162, "28038": 0.15777134895324707, "28290": 0.05046287178993225, "28487": 0.9186317324638367, "28756": 0.7201237678527832, "28767": 1.060796856880188, "28873": 0.4500300884246826, "29147": 1.3464484214782715, "29206": 0.1229778528213501, "29720": 0.4437839686870575} | 24530130 | The gene encoding apolipoprotein E (APOE) on chromosome 19 is the only confirmed susceptibility locus for late-onset Alzheimer's disease. To identify other risk loci, we conducted a large genome-wide association study of 2,032 individuals from France with Alzheimer's disease (cases) and 5,328 controls. Markers outside APOE with suggestive evidence of association (P < 10−5) were examined in collections from Belgium, Finland, Italy and Spain totaling 3,978 Alzheimer's disease cases and 3,297 controls. Two loci gave replicated evidence of association: one within CLU (also called APOJ), encoding clusterin or apolipoprotein J, on chromosome 8 (rs11136000, OR = 0.86, 95% CI 0.81–0.90, P = 7.5 × 10−9 for combined data) and the other within CR1, encoding the complement component (3b/4b) receptor 1, on chromosome 1 (rs6656401, OR = 1.21, 95% CI 1.14–1.29, P = 3.7 × 10−9 for combined data). Previous biological studies support roles of CLU and CR1 in the clearance of β amyloid (Aβ) peptide, the principal constituent of amyloid plaques, which are one of the major brain lesions of individuals with Alzheimer's disease. | Genome-wide association study identifies variants at CLU and CR1 associated with Alzheimer's disease |
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1.1063944101333618, "24587": 0.04767346754670143, "24848": 1.0158531665802002, "24854": 0.9021284580230713, "25101": 1.0271050930023193, "25714": 0.8315495252609253, "26083": 0.015504186972975731, "26305": 0.25694093108177185, "26524": 0.0038986403960734606, "26563": 0.14939609169960022, "26874": 0.010684899985790253, "27321": 0.0606246218085289, "27381": 0.07341018319129944, "28086": 1.4821370840072632, "28156": 0.3923587501049042, "28405": 0.10731173306703568, "28691": 0.09584271162748337, "28723": 0.13157635927200317, "28788": 0.4770587682723999, "28873": 0.02792670577764511, "29280": 0.10291612148284912} | 24530633 | Embryonic stem (ES) cells are pluripotent cells derived from the inner cell mass (ICM) and the epiblast, and have been suggested to be a homogeneous population with characteristics intermediate between them. These cells express Oct3/4 and Rex1 genes, which have been used as markers to indicate the undifferentiated state of ES cells. Whereas Oct3/4 is expressed in totipotent and pluripotent cells in the mouse life cycle, Rex1 expression is restricted to the ICM, and is downregulated in pluripotent cell populations in the later stages, i.e. the epiblast and primitive ectoderm (PrE). To address whether ES cells comprise a homogeneous population equivalent to a certain developmental stage of pluripotent cells or a heterogeneous population composed of cells corresponding to various stages of differentiation, we established knock-in ES cell lines in which genes for fluorescent proteins were inserted into the Rex1 and Oct3/4 gene loci to visualize the expression of these genes. We found that undifferentiated ES cells included at least two different populations, Rex1(+)/Oct3/4(+) cells and Rex1(-)/Oct3/4(+) cells. The Rex1(-)/Oct3/4(+) and Rex1(+)/Oct3/4(+) populations could convert into each other in the presence of LIF. In accordance with our assumption that Rex1(+)/Oct3/4(+) cells and Rex1(-)/Oct3/4(+) cells have characteristics similar to those of ICM and early-PrE cells, Rex1(+)/Oct3/4(+) cells predominantly differentiated into primitive ectoderm and contributed to chimera formation, whereas Rex1(-)/Oct3/4(+) cells differentiated into cells of the somatic lineage more efficiently than non-fractionated ES cells in vitro and showed poor ability to contribute to chimera formation. These results confirmed that undifferentiated ES cell culture contains subpopulations corresponding to ICM, epiblast and PrE. | Identification and characterization of subpopulations in undifferentiated ES cell culture. |
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1.0285027027130127, "27059": 0.022212404757738113, "27152": 1.2387138605117798, "27226": 0.11778303235769272, "27375": 0.015504186972975731, "27521": 0.18004031479358673, "27777": 0.040196798741817474, "28024": 0.151916041970253, "28156": 0.3824150264263153, "28324": 0.1905880719423294, "28389": 0.3409265875816345, "28406": 0.5973974466323853, "28424": 0.18573370575904846, "28691": 0.1913948506116867, "28846": 0.16690383851528168, "29139": 0.0354953333735466, "29174": 0.524982750415802, "29366": 0.037378571927547455} | 24541180 | Current methods of nuclear isolation from liver disrupt the plasmalemmae via homogenization and separation of the nuclei by high centrifugal force (HCF) through gradients of sucrose or other substances for up to 80 min. The use of HCF for such a long time increases the potential for nuclear damage and degradation by endogenous proteases. We compared four combinations of alterations to classical nuclear isolation methods as follows. Mouse liver was gently crushed through a fine mesh with and without in vivo perfusion with collagenase. The cell suspension was centrifuged at 600 g to remove gross debris and then at moderate centrifugal force (MCF, 16,000 g) or high centrifugal force (HCF, 70,000 g) through sucrose gradients for 30 min. The purity of the isolated nuclei was assessed biologically and morphologically, including analyses of representative marker proteins for nuclei and cytoplasm. The results indicate that MCF and no collagenase provided the highest nuclear integrity and purity, whereas MCF with collagenase is a viable option if priority is given to yield. The method is especially suited for small samples and so should facilitate studies with human liver biopsies and livers from mice, the most widely used species for gene targeting. | Isolation of intact nuclei of high purity from mouse liver. |
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In Escherichia coli, NusG suppresses pausing and increases elongation rate, enhances termination by E. coli rho and phage HK022 Nun protein, and promotes antitermination by lambdaN and in ribosomal RNA operons. We report NMR studies that suggest that E. coli NusG consists of two largely independent N- and C-terminal structural domains, NTD and CTD, respectively. Based on tests of the functions of the NTD and CTD and variants of NusG in vivo and in vitro, we find that NTD alone is sufficient to suppress pausing and enhance transcript elongation in vitro. However, neither domain alone can enhance rho-dependent termination or support antitermination, indicating that interactions of both domains with ECs are required for these processes. We propose that the two domains of NusG mediate distinct interactions with ECs: the NTD interacts with RNA polymerase and the CTD interacts with rho and other regulators, providing NusG with different combinations of interactions to effect different regulatory outcomes. | Two structurally independent domains of E. coli NusG create regulatory plasticity via distinct interactions with RNA polymerase and regulators. |
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"24558": 0.26146242022514343, "24635": 0.14349138736724854, "24895": 0.05786345899105072, "25022": 0.011650617234408855, "25057": 0.0770333781838417, "25181": 0.11778303235769272, "25206": 0.012615402229130268, "25456": 1.1005635261535645, "25458": 0.31560876965522766, "25524": 0.45623743534088135, "26228": 0.01934296265244484, "26235": 0.30989447236061096, "26402": 0.5947071313858032, "26461": 0.2539152204990387, "26471": 0.4500300884246826, "26572": 0.48068851232528687, "26703": 0.29036402702331543, "26721": 0.8901712894439697, "26944": 0.32553088665008545, "27094": 0.5461324453353882, "28032": 0.6813592314720154, "28086": 0.7889899015426636, "28329": 0.3750596046447754, "28426": 0.5051454305648804, "28436": 0.43875885009765625, "28648": 0.7995813488960266, "28699": 0.06977381557226181, "28911": 0.1221139207482338, "28993": 0.7482418417930603, "29105": 0.13071982562541962} | 24552097 | BACKGROUND In the plant sciences there are two widely applied technologies for measuring nuclear DNA content: Feulgen absorbance cytophotometry and flow cytometry (FCM). While FCM is, with good reasons, increasingly popular among plant scientists, absorbance-cytophotometric techniques lose ground. This results in a narrowing of the methodological repertoire, which is neither desirable nor beneficial. Both approaches have their advantages, but static cytophotometry seems to pose more instrumental difficulties and material-based problems than FCM, so that Feulgen-based data in the literature are often less reliable than one would expect. SCOPE The purpose of this article is to present a selective overview of the field of nuclear DNA content measurement, and C-values in particular, with a focus on the technical difficulties imposed by the characteristics of the biological material and with some comments on the photometrical aspects of the work. For over 20 years it has been known that plant polyphenols cause problems in Feulgen DNA cytophotometry, since they act as major staining inhibitors leading to unreliable results. However, little information is available about the chemical classes of plant metabolites capable of DNA staining interference and the mechanisms of their inhibition. Plant slimes are another source of concern. CONCLUSIONS In FCM research to uncover the effects of secondary metabolites on measurement results has begun only recently. In particular, the analysis of intraspecific genome size variation demands a stringent methodology which accounts for inhibitors. FCM tests for inhibitory effects of endogenous metabolites should become obligatory. The use of dry seeds for harvesting embryo and endosperm nuclei for FCM and Feulgen densitometry may often provide a means of circumventing staining inhibitors. The importance of internal standardization is highlighted. Our goal is a better understanding of phytochemical/cytochemical interactions in plant DNA photometry for the benefit of an ever-growing list of plant genome sizes. | Cytochemistry and C-values: the less-well-known world of nuclear DNA amounts. |
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This regulation is mediated by G1 phase cyclin-dependent kinases (CDKs), which are downstream of signaling pathways under the integrated control of both integrins and growth factor receptors. Recent advances demonstrate a surprisingly diverse array of integrin-dependent signals that are channeled into the regulation of the G1 phase CDKs. Regulation of cyclin D1 by the ERK pathway may provide a paradigm for understanding how cell adhesion can determine cell cycle progression. | Integrins and cell proliferation: regulation of cyclin-dependent kinases via cytoplasmic signaling pathways. |
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0.08244366943836212, "28086": 0.010684899985790253, "28251": 1.3118107318878174, "28369": 0.18411032855510712, "28424": 0.1332872211933136, "28691": 0.11865071207284927, "28788": 0.5800528526306152, "28828": 0.05786345899105072, "28829": 0.053244512528181076, "29060": 0.36290550231933594, "29129": 0.025073638185858727, "29228": 0.1913948506116867} | 24555417 | In many species, oocyte meiosis is carried out in the absence of centrioles. As a result, microtubule organization, spindle assembly, and chromosome segregation proceed by unique mechanisms. Here, we report insights into the principles underlying this specialized form of cell division, through studies of C. elegans KLP-15 and KLP-16, two highly homologous members of the kinesin-14 family of minus-end-directed kinesins. These proteins localize to the acentriolar oocyte spindle and promote microtubule bundling during spindle assembly; following KLP-15/16 depletion, microtubule bundles form but then collapse into a disorganized array. Surprisingly, despite this defect we found that during anaphase, microtubules are able to reorganize into a bundled array that facilitates chromosome segregation. This phenotype therefore enabled us to identify factors promoting microtubule organization during anaphase, whose contributions are normally undetectable in wild-type worms; we found that SPD-1 (PRC1) bundles microtubules and KLP-18 (kinesin-12) likely sorts those bundles into a functional orientation capable of mediating chromosome segregation. Therefore, our studies have revealed an interplay between distinct mechanisms that together promote spindle formation and chromosome segregation in the absence of structural cues such as centrioles. | Interplay between microtubule bundling and sorting factors ensures acentriolar spindle stability during C. elegans oocyte meiosis |
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"25095": 0.12814582884311676, "25531": 0.011650617234408855, "25551": 0.026976587250828743, "25636": 0.0174254160374403, "25854": 0.36900100111961365, "26147": 0.10731173306703568, "26226": 0.27712854743003845, "26236": 0.20739519596099854, "26264": 0.15526613593101501, "26319": 0.013579257763922215, "27354": 0.6016870141029358, "27615": 0.12384103983640671, "27833": 0.25467249751091003, "28093": 0.40806588530540466, "28329": 0.06520967930555344, "28353": 0.3170322775840759, "29278": 0.0354953333735466, "29458": 0.4944818615913391} | 24555878 | This paper describes a paper and pencil questionnaire that measures heart disease risk knowledge in people with diabetes. The Heart Disease Fact Questionnaire (HDFQ) is a 25-item questionnaire that was developed to tap into respondents' knowledge of major risk factors for the development of CHD. Approximately half of these items specifically address diabetes-related CHD risk factors. Based on extensive pilot data, the current study analyzed responses from 524 people with diabetes to assess the psychometric properties. The HDFQ is readable to an average 13-year old and imposes little burden. It shows good content and face validity. It demonstrates adequate internal consistency, with Kuder-Richardson-20 formula = 0.77 and good item-total correlations. Item analysis showed a desirable range in P-values. In discriminant function analyses, HDFQ scores differentiated respondents by knowledge of their own cardiovascular health, use of lipid lowering medications, health insurance status, and educational attainment, thus indicating good criterion related validity. This measure of heart disease risk knowledge is brief, understandable to respondents, and easy to administer and score. Its potential for use in research and practice is discussed. Future research should establish norms as well as investigate its test-retest reliability and predictive validity. | Development of a questionnaire to measure heart disease risk knowledge in people with diabetes: the Heart Disease Fact Questionnaire. |
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0.9084475636482239, "27102": 0.24171993136405945, "27197": 0.7491656541824341, "27229": 0.41065993905067444, "27511": 0.2822965085506439, "27794": 0.08244366943836212, "27875": 0.08692999184131622, "28093": 0.4002431631088257, "28297": 0.18978065252304077, "28321": 0.5601736903190613, "28418": 0.14686977863311768, "28436": 0.812664806842804, "28498": 0.08244366943836212, "28975": 1.4037197828292847, "29125": 0.021256839856505394, "29215": 0.5751199722290039, "29458": 0.007782140281051397} | 24557631 | Background: The prevalence of multiple sclerosis (MS) shows considerable variability all over the world. According to Kurtzke, Iran is considered to have a low prevalence. Objective: To estimate the period prevalence and risk factors of MS in Isfahan, central part of Iran. Methods: A cross-sectional case register study conducted between 2004 and 2005. In the province of Isfahan, Iran, all patients known to have definite MS during 2004 and 2005, being alive and resident within Isfahan as well as being a member of the Isfahan MS Association were included in the study. Demographic and case-related information was recorded. 1,391 definite MS patients (308 men and 1,083 women) from the Isfahan MS Association, Iran, have been identified. The disease was confirmed using clinical information and MRI findings by a neurologist and radiologist. The patients were evaluated by interview and a questionnaire. Population data were obtained from the year 1999 Iran Census. The mean (SD) age of the participants was 32.5 (9.3) years with a mean (SD) duration of the disease of 6.4 (5.1) years for men and 6.9 (5.3) years for women. Results: The period prevalence of MS was 35.5 per 100,000 [95% confidence interval (CI) 33.6–37.3] in a population of 3,923,255, with a higher rate in women than men [54.5 (95% CI: 51.1–57.8) for women and 14.9 (95% CI: 13.3–16.6) for men]. The female/male ratio was 3.6 (95% CI: 3.2–4.1). The direct age-adjusted period prevalence was 59.5 per 100,000 (95% CI: 44.8–75.2) for women and 17.0 per 100,000 (95% CI: 8.9–25.1) for men. MS rates were highest among 30- to 39-year-olds and decreased with increasing age. Sensory and visual disturbances were the most common initial presentations with a prevalence of 51.1% (95% CI: 48.4–53.7) and 47.0% (95% CI: 44.4–49.7), respectively. Conclusion: Isfahan could be considered as an area with a medium to high risk of MS. This is in sharp contrast with the gradient hypothesis. | Prevalence of Multiple Sclerosis in Isfahan, Iran |
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"23247": 0.13670019805431366, "23303": 0.5941681861877441, "23371": 0.24171993136405945, "23931": 0.417115718126297, "24137": 0.32199856638908386, "24382": 1.0735615491867065, "24939": 0.07250232994556427, "25032": 0.9447870850563049, "25426": 0.07884006202220917, "25705": 0.2852376699447632, "26083": 0.22704219818115234, "26285": 0.15777134895324707, "26520": 0.3723714053630829, "26773": 0.6327666640281677, "26874": 1.3326339721679688, "27152": 0.5104349255561829, "27642": 0.9371650815010071, "27777": 0.2711893916130066, "27822": 1.0285027027130127, "28024": 0.09495500475168228, "28041": 0.09406650811433792, "28086": 0.0019512200960889459, "28251": 1.0560526847839355, "28788": 0.678885817527771, "29129": 0.04674193635582924} | 24558930 | Although assembly of acentrosomal meiotic spindles has been extensively studied, little is known about the segregation of chromosomes on these spindles. Here, we show in Caenorhabditis elegans oocytes that the kinetochore protein, KNL-1, directs assembly of meiotic kinetochores that orient chromosomes. However, in contrast to mitosis, chromosome separation during meiotic anaphase is kinetochore-independent. Before anaphase, meiotic kinetochores and spindle poles disassemble along with the microtubules on the poleward side of chromosomes. During anaphase, microtubules then form between the separating chromosomes. Functional analysis implicated a set of proteins that localize to a ring-shaped domain between kinetochores during pre-anaphase spindle assembly and anaphase separation. These proteins are localized by the chromosomal passenger complex, which regulates the loss of meiotic chromosome cohesion. Thus, meiotic segregation in C. elegans is a two-stage process, where kinetochores orient chromosomes, but are then dispensable for their separation. We suggest that separation is controlled by a meiosis-specific chromosomal domain to coordinate cohesin removal and chromosome segregation. | A kinetochore-independent mechanism drives anaphase chromosome separation during acentrosomal meiosis |
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"25481": 0.5612884759902954, "25525": 0.32058215141296387, "25640": 0.34023189544677734, "25778": 0.3262358605861664, "25918": 0.0019512200960889459, "26465": 0.5318912267684937, "26745": 0.4437839686870575, "26913": 0.07612881064414978, "27140": 0.25088030099868774, "27144": 1.3086495399475098, "27292": 0.04953393340110779, "27364": 0.8885661959648132, "27615": 1.2819099426269531, "27844": 0.056018441915512085, "28032": 0.052318159490823746, "28393": 0.9333322048187256, "28436": 0.013579257763922215, "28507": 0.15610189735889435, "28518": 0.026976587250828743, "28804": 0.19622190296649933, "28877": 0.01934296265244484, "29172": 0.24171993136405945, "29191": 0.11168810725212097, "29234": 0.2493593990802765, "29277": 0.17840765416622162} | 24575065 | CONTEXT The Medicare Prescription Drug, Improvement, and Modernization Act of 2003 (MMA) altered reimbursements for outpatient chemotherapy drugs and drug administration services. Anecdotal reports suggest that these adjustments may have negatively affected access to chemotherapy for Medicare beneficiaries. OBJECTIVE To compare patient wait times and travel distances for chemotherapy before and after the enactment of the MMA. DESIGN, SETTING, AND PATIENTS Analysis of a nationally representative 5% sample of claims from the Centers for Medicare & Medicaid Services for the period 2003 through 2006. Patients were Medicare beneficiaries with incident breast cancer, colorectal cancer, leukemia, lung cancer, or lymphoma who received chemotherapy in inpatient hospital, institutional outpatient, or physician office settings. MAIN OUTCOME MEASURES Days from incident diagnosis to first chemotherapy visit and distance traveled for treatment, controlling for age, sex, race/ethnicity, cancer type, geographic region, comorbid conditions, and year of diagnosis and treatment. RESULTS There were 5082 incident cases of breast cancer, colorectal cancer, leukemia, lung cancer, or lymphoma in 2003; 5379 cases in 2004; 5116 cases in 2005; and 5288 cases in 2006. Approximately 70% of patients received treatment in physician office settings in each year. Although the distribution of treatment settings in 2004 and 2005 was not significantly different from 2003 (P = .24 and P = .72, respectively), there was a small but significant change from 2003 to 2006 (P = .02). The proportion of patients receiving chemotherapy in inpatient settings decreased from 10.2% in 2003 to 8.8% in 2006 (P = .03), and the proportion in institutional outpatient settings increased from 21.1% to 22.5% (P = .004). The proportion in physician offices remained at 68.7% (P = .29). The median time from diagnosis to initial chemotherapy visit was 28 days in 2003, 27 days in 2004, 29 days in 2005, and 28 days in 2006. In multivariate analyses, average wait times for chemotherapy were 1.96 days longer in 2005 than in 2003 (95% confidence interval [CI], 0.11-3.80 days; P = .04) but not significantly different in 2006 (0.88 days; 95% CI, -0.96 to 2.71 days; P = .35). Median travel distance was 7 miles (11.2 km) in 2003 and 8 miles (12.8 km) in 2004 through 2006. After adjustment, average travel distance remained slightly longer in 2004 (1.47 miles [2.35 km]; 95% CI, 0.87-2.07 miles [1.39-3.31 km]; P < .001), 2005 (1.19 miles [1.90 km]; 95% CI, 0.58-1.80 miles [0.93-2.88 km]; P < .001), and 2006 (1.30 miles [2.08 km]; 95% CI, 0.69-1.90 miles [1.10-3.04 km]; P < .001) compared with 2003. CONCLUSION There have not been major changes in travel distance and patient wait times for chemotherapy in the Medicare population since 2003, the year before MMA-related changes in reimbursement. | Association between the Medicare Modernization Act of 2003 and patient wait times and travel distance for chemotherapy. |
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0.05694137513637543, "29458": 0.19622190296649933, "29494": 0.1011524572968483} | 24581365 | CONTEXT The appropriate therapy for men with clinically localized prostate cancer is uncertain. A recent study suggested an increasing prostate cancer mortality rate for men who are alive more than 15 years following diagnosis. OBJECTIVE To estimate 20-year survival based on a competing risk analysis of men who were diagnosed with clinically localized prostate cancer and treated with observation or androgen withdrawal therapy alone, stratified by age at diagnosis and histological findings. DESIGN, SETTING, AND PATIENTS A retrospective population-based cohort study using Connecticut Tumor Registry data supplemented by hospital record and histology review of 767 men aged 55 to 74 years with clinically localized prostate cancer diagnosed between January 1, 1971, and December 31, 1984. Patients were treated with either observation or immediate or delayed androgen withdrawal therapy, with a median observation of 24 years. MAIN OUTCOME MEASURES Probability of mortality from prostate cancer or other competing medical conditions, given a patient's age at diagnosis and tumor grade. RESULTS The prostate cancer mortality rate was 33 per 1000 person-years during the first 15 years of follow-up (95% confidence interval [CI], 28-38) and 18 per 1000 person-years after 15 years of follow-up (95% CI, 10-29). The mortality rates for these 2 follow-up periods were not statistically different, after adjusting for differences in tumor histology (rate ratio, 1.1; 95% CI, 0.6-1.9). Men with low-grade prostate cancers have a minimal risk of dying from prostate cancer during 20 years of follow-up (Gleason score of 2-4, 6 deaths per 1000 person-years; 95% CI, 2-11). Men with high-grade prostate cancers have a high probability of dying from prostate cancer within 10 years of diagnosis (Gleason score of 8-10, 121 deaths per 1000 person-years; 95% CI, 90-156). Men with Gleason score of 5 or 6 tumors have an intermediate risk of prostate cancer death. CONCLUSION The annual mortality rate from prostate cancer appears to remain stable after 15 years from diagnosis, which does not support aggressive treatment for localized low-grade prostate cancer. | 20-year outcomes following conservative management of clinically localized prostate cancer. |
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Chronic beta(1)AR activation is implicated in the pathogenesis of HF and betaAR blockade improves survival in left ventricular systolic dysfunction. Common functional polymorphisms in beta adrenergic receptor genes (ADRB) have been associated with HF phenotypes, and with pharmacogenetic interaction with beta adrenergic receptor blockers (beta blockers). However, these associations have not been consistently replicated. The evidence for ADRB variant involvement in pathogenesis, progression and response to beta blockers in HF is reviewed. In addition, a meta-analysis of three studies analysing the effect of ADRB1 Arg389Gly polymorphism on left ventricular remodelling with the use of beta blockers, demonstrating a 5% improvement in left ventricular ejection fraction in Arg389 homozygotes, is presented. There is now accumulating molecular evidence for a different functional response to beta blockers associated with this polymorphism. In the future, confirmed genotypic associations may enable patients to be identified who are either at greater risk of developing HF, whose HF may rapidly progress, or who are unlikely to benefit from beta blockers, and such patients may benefit from targeted aggressive therapy. | Role of beta adrenergic receptor polymorphisms in heart failure: systematic review and meta-analysis. |
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With the rising prevalence of type 2 diabetes mellitus and obesity in women of childbearing age, diabetes mellitus-induced birth defects have become an increasingly significant public health problem. Maternal diabetes mellitus in vivo and high glucose in vitro induce yolk sac injuries by damaging the morphologic condition of cells and altering the dynamics of organelles. The yolk sac vascular system is the first system to develop during embryogenesis; therefore, it is the most sensitive to hyperglycemia. The consequences of yolk sac injuries include impairment of nutrient transportation because of vasculopathy. Although the functional relationship between yolk sac vasculopathy and structural birth defects has not yet been established, a recent study reveals that the quality of yolk sac vasculature is related inversely to embryonic malformation rates. Studies in animal models have uncovered key molecular intermediates of diabetic yolk sac vasculopathy, which include hypoxia-inducible factor-1α, apoptosis signal-regulating kinase 1, and its inhibitor thioredoxin-1, c-Jun-N-terminal kinases, nitric oxide, and nitric oxide synthase. Yolk sac vasculopathy is also associated with abnormalities in arachidonic acid and myo-inositol. Dietary supplementation with fatty acids that restore lipid levels in the yolk sac lead to a reduction in diabetes mellitus-induced malformations. Although the role of the human yolk in embryogenesis is less extensive than in rodents, nevertheless, human embryonic vasculogenesis is affected negatively by maternal diabetes mellitus. Mechanistic studies have identified potential therapeutic targets for future intervention against yolk sac vasculopathy, birth defects, and other complications associated with diabetic pregnancies. | New development of the yolk sac theory in diabetic embryopathy: molecular mechanism and link to structural birth defects. |
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of coinfection with either hepatitis B or C on the clinical course in patients infected with the human immunodeficiency virus (HIV). METHODS Follow-up was available in 232 HIV-infected patients (age 37+/-8 years, CD4 count 167+/-167 microl; 46% had AIDS). Samples were investigated for markers of HBV and HCV infection (HBsAg, HBeAg, HBV-DNA, Anti-HBs, anti-HBc, anti-HCV, HCV-RNA). RESULTS 60/232 patients (23%) were anti-HCV positive. 78% of these sera were positive for HCV-RNA. 22/232 patients (9%) suffered from chronic HBV infection (HBsAg positive), 18/22 (82%) of these sera had detectable HBeAg and 19/22 (86%) HBV-DNA. Presence of HCV-RNA, HBeAg and amount of HBV-DNA were related to the degree of immunodeficiency. In contrast to the control group without HBV or HCV infection, patients infected with HIV and either HBV or HCV showed a direct correlation between a reduction in CD4 counts and decreased cholinesterase activity. In patients with AIDS, coinfection with HBV or HCV was associated with a reduced survival compared to controls (HBV: 212 days, 95%CI, 106-317; HCV: 267, 95%CI, 112-396; controls: 439 days, 95%CI, 364-513). CONCLUSIONS Coinfection of HIV and HBV or HCV is frequently observed. Our results suggest that with prolonged survival of HIV-infected patients, coinfection with either HBV or HCV correlates with a reduced survival rate. | Hepatitis B and C in HIV-infected patients. Prevalence and prognostic value. |
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"29490": 0.09050461649894714} | 24612804 | IL-17 is a novel, CD4+ T cell-restricted cytokine. In vivo, it stimulates hematopoiesis and causes neutrophilia consisting of mature granulocytes. In this study, we show that IL-17-mediated granulopoiesis requires G-CSF release and the presence or induction of the transmembrane form of stem cell factor (SCF) for optimal granulopoiesis. However, IL-17 also protects mice from G-CSF neutralization-induced neutropenia. G-CSF neutralization completely reversed IL-17-induced BM progenitor expansion, whereas splenic CFU-GM/CFU-granulocyte-erythrocyte-megakaryocyte-monocyte was only reduced by 50% in both Sl/Sld and littermate control mice. Thus, there remained a significant SCF/G-CSF-independent effect of IL-17 on splenic granulopoiesis, resulting in a preservation of mature circulating granulocytes. IL-17 is a cytokine that potentially interconnects lymphocytic and myeloid host defense and may have potential for therapeutic development. | Requirement of endogenous stem cell factor and granulocyte-colony-stimulating factor for IL-17-mediated granulopoiesis. |
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cell-type- and stimulus-dependent fashion, the early response gene immediate early gene X-1 (IEX-1) is involved in growth control and modulation of apoptosis. The present study demonstrates that, in the two acute promyelocytic leukemia (APL) cell lines NB4 and KG1, exhibiting distinct responsiveness to retinoic acids (RAs), IEX-1 expression is rapidly (30–60 min) induced by all-trans- or cis-RA and independently of other signal transduction mediators, such as TNFα, NF-κB or MAP kinases. In NB4 cells (expressing PML–RARα), this increase is transient and completely reversible, along with a cell cycle arrest, ongoing differentiation and lower sensitivity to anti-cancer-drug-induced apoptosis. In contrast, the RA-induced IEX-1 expression in KG1 cells (expressing PLZF–RARα) persists over days, along with continued cell cycle progression and increased apoptotic sensitivity. Furthermore, two functional RA-response elements in the IEX-1 promoter were identified by gel shift and luciferase reporter gene assays. IEX-1 might be a rather unique transcriptional target of the two X–RARα fusion receptors exhibiting distinct responsiveness to RAs. Following a different time course of direct transcriptional induction by PML–RARα and PLZF–RARα in NB4 and KG1 cells, respectively, IEX-1 expression may be involved in the modified actions of these receptors and the distinct phenotypes of APL cells. | The expression of immediate early gene X-1 (IEX-1) is differentially induced by retinoic acids in NB4 and KG1 cells: possible implication in the distinct phenotype of retinoic acid-responsive and -resistant leukemic cells |
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In this article, we systematically review and critically discuss evidence on the prevalence of ADHD in obese patients as well as the weight status of individuals with ADHD. Relevant articles were searched in PubMed, PsychInfo, and ISI Web of Science (January 1980 to June 2010). We found that current evidence indicates a high prevalence of ADHD in clinical samples of patients seeking treatment for their obesity. Moreover, available studies show that individuals with ADHD have higher-than-average body mass index z scores and/or a significantly higher prevalence of obesity compared with subjects without ADHD. Three mechanisms underlying the association between ADHD and obesity have been proposed: 1) it is possible that obesity and/or factors associated with it (such as sleep-disordered breathing) manifest as ADHD-like symptoms; 2) ADHD and obesity share common biological dysfunctions; and 3) ADHD contributes to obesity. With regards to the possible clinical implications, our findings suggest that it is noteworthy to screen for ADHD in patients with obesity and to look for abnormal eating behaviors as possible contributing factors of obesity in patients with ADHD. Based on preliminary findings, appropriate treatment of ADHD may improve the weight status of individuals with both obesity and ADHD. | Comorbidity between ADHD and obesity: exploring shared mechanisms and clinical implications. |
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"29215": 0.8885661959648132, "29295": 0.4932899475097656, "29494": 0.75193190574646, "29516": 0.04767346754670143} | 24632480 | Aberrant protein misfolding may contribute to the pathogenesis of amyotrophic lateral sclerosis (ALS) but the detailed mechanisms are largely unknown. Our previous study has shown that autophagy is altered in the mouse model of ALS. In the present study, we systematically investigated the correlation of the autophagic alteration with the motor neurons (MNs) degeneration in the ALS mice. We have demonstrated that the autophagic protein marker LC3-II is markedly and specifically increased in the spinal cord MNs of the ALS mice. Electron microscopy and immunochemistry studies have shown that autophagic vacuoles are significantly accumulated in the dystrophic axons of spinal cord MNs of the ALS mice. All these changes in the ALS mice appear at the age of 90 d when the ALS mice display modest clinical symptoms; and they become prominent at the age of 120 d. The clinical symptoms are correlated with the progression of MNs degeneration. Moreover, we have found that p62/SQSTM1 is accumulated progressively in the spinal cord, indicating that the possibility of impaired autophagic flux in the SOD1(G93A) mice. Furthermore, to our surprise, we have found that treatment with autophagy enhancer rapamycin accelerates the MNs degeneration, shortens the life span of the ALS mice, and has no obvious effects on the accumulation of SOD1 aggregates. In addition, we have demonstrated that rapamycin treatment in the ALS mice causes more severe mitochondrial impairment, higher Bax levels and greater caspase-3 activation. These findings suggest that selective degeneration of MNs is associated with the impairment of the autophagy pathway and that rapamycin treatment may exacerbate the pathological processing through apoptosis and other mechanisms in the ALS mice. | Rapamycin treatment augments motor neuron degeneration in SOD1(G93A) mouse model of amyotrophic lateral sclerosis. |
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0.1751343309879303} | 24634621 | PURPOSE Most patients with advanced pancreas cancer experience pain and must limit their daily activities because of tumor-related symptoms. To date, no treatment has had a significant impact on the disease. In early studies with gemcitabine, patients with pancreas cancer experienced an improvement in disease-related symptoms. Based on those findings, a definitive trial was performed to assess the effectiveness of gemcitabine in patients with newly diagnosed advanced pancreas cancer. PATIENTS AND METHODS One hundred twenty-six patients with advanced symptomatic pancreas cancer completed a lead-in period to characterize and stabilize pain and were randomized to receive either gemcitabine 1,000 mg/m2 weekly x 7 followed by 1 week of rest, then weekly x 3 every 4 weeks thereafter (63 patients), or to fluorouracil (5-FU) 600 mg/m2 once weekly (63 patients). The primary efficacy measure was clinical benefit response, which was a composite of measurements of pain (analgesic consumption and pain intensity), Karnofsky performance status, and weight. Clinical benefit required a sustained (> or = 4 weeks) improvement in at least one parameter without worsening in any others. Other measures of efficacy included response rate, time to progressive disease, and survival. RESULTS Clinical benefit response was experienced by 23.8% of gemcitabine-treated patients compared with 4.8% of 5-FU-treated patients (P = .0022). The median survival durations were 5.65 and 4.41 months for gemcitabine-treated and 5-FU-treated patients, respectively (P = .0025). The survival rate at 12 months was 18% for gemcitabine patients and 2% for 5-FU patients. Treatment was well tolerated. CONCLUSION This study demonstrates that gemcitabine is more effective than 5-FU in alleviation of some disease-related symptoms in patients with advanced, symptomatic pancreas cancer. Gemcitabine also confers a modest survival advantage over treatment with 5-FU. | Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. |
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"28086": 0.04860413447022438, "28156": 0.7445381283760071, "28353": 0.9425065517425537, "28522": 0.9613537192344666, "28691": 0.0842406153678894, "28696": 0.0009760859538801014, "28788": 0.19862671196460724, "28815": 0.09495500475168228, "29105": 0.8893690705299377, "29107": 0.013579257763922215, "29129": 0.7528522610664368, "29290": 0.4437839686870575} | 24640046 | Diabetic nephropathy is the leading cause of chronic renal failure. Myofibroblasts play a major role in the synthesis and secretion of extracellular matrix in diabetic renal fibrosis. Increasing evidence suggests that endothelial cells may undergo endothelial-myofibroblast transition under physiological and pathophysiological circumstances. Therefore, this study investigates whether endothelial-myofibroblast transition occurs and contributes to the development of diabetic renal interstitial fibrosis. Diabetes was induced by administration of streptozotocin to Tie2-Cre;LoxP-EGFP mice, an endothelial lineage-traceable mouse line generated by crossbreeding B6.Cg-Tg(Tek-cre)12F1v/J mice with B6.Cg-Tg(ACTB-Bgeo/GFP)21Lbe/J mice. The endothelial-myofibroblast transition was also studied in MMECs (a mouse pancreatic microvascular endothelial cell line) and primary cultures of CD31+/EYFP- (enhanced yellow fluorescent protein) endothelial cells isolated from adult normal alpha-smooth muscle actin promoter-driven-EYFP (alpha-SMA/EYFP) mouse kidneys. Confocal microscopy demonstrated that 10.4 +/- 4.2 and 23.5 +/- 7.4% of renal interstitial myofibroblasts (alpha-SMA+) in 1- and 6-month streptozotocin-induced diabetic kidneys were of endothelial origin (EGFP+/alpha-SMA+ cells), compared with just 0.2 +/- 0.1% of myofibroblasts in vehicle-treated Tie2-Cre;LoxP-EGFP mice (P < 0.01). Confocal microscopy and real-time PCR showed that transforming growth factor (TGF)-beta1 induced de novo expression of alpha-SMA and loss of expression of VE-cadherin and CD31 in MMECs and primary cultures of renal endothelial cells in a time- and dose-dependent fashion. These findings demonstrate that the endothelial-myofibroblast transition occurs and contributes to the early development and progression of diabetic renal interstitial fibrosis and suggest that the endothelial-myofibroblast transition may be a therapeutic target. | Endothelial-myofibroblast transition contributes to the early development of diabetic renal interstitial fibrosis in streptozotocin-induced diabetic mice. |
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"28164": 0.04767346754670143, "28251": 0.4450363218784332, "28373": 0.02792670577764511, "28432": 0.26446542143821716, "28691": 0.04674193635582924, "28815": 0.28890204429626465, "28828": 0.15442965924739838, "28848": 0.6624060273170471, "29290": 0.33115679025650024, "29295": 0.15442965924739838, "29490": 0.4248080551624298, "29494": 0.053244512528181076, "29720": 0.42353010177612305, "29721": 0.2539152204990387} | 24645237 | The coloured ciliate Blepharisma japonicum changes swimming velocity (positive photokinesis) and elongates its body in response to a prolonged illumination. We have recently proposed that alterations in the phosphorylation level of the ciliate phosducin (Pdc) may be involved in light-induced cell elongation, which in turn affects the interaction of βγ-dimer of G-proteins (Gβγ) with β-tubulin and subsequent cytoskeletal remodelling. The cellular mechanism that governs the photokinetic effect in this ciliate has not been elucidated. In the present study, we utilise real-time PCR to demonstrate that the levels of ciliate Pdc mRNA are significantly reduced in Pdc-RNAi-treated cells compared to cells fed with bacteria carrying the empty vector (control cells). Using western immunoblotting, we confirmed that these cells treated with Pdc-RNAi expressed a substantially lower level of the Pdc protein. The assay also revealed that in ciliates treated with Pdc-RNAi and exposed to light, the cytosolic level of Gβ (~36 kDa) was reduced, whereas the level of Gβ localized to the membrane (~32 kDa) was increased compared to control cells. In addition, behavioural analysis of the cells indicated a substantial reduction of photokinesis. The findings in this study provide additional characterization of the functional properties of the ciliate Pdc protein and we discuss a likely role for this phosphoprotein in the photokinetic phenomenon of the ciliate protist Blepharisma. | Effect of phosducin silencing on the photokinetic motile response of Blepharisma japonicum. |
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(AD). Proper function and morphology of BFCNs depends on the supply of nerve growth factor (NGF) from the cortex and the hippocampus. A large number of experiments have shown that decreased supply of NGF at the level of BFCN cell bodies leads to loss of neuronal markers and shrinkage, mimicking what is observed in AD. The delivery of sufficient amounts of NGF signal to BFCN cell bodies depends on the effective participation of several factors including sufficient synthesis and release of NGF, adequate synthesis and expression of NGF receptors by BFCNs, normal signaling and retrograde transport of NGF-receptor complex, and finally effective induction of gene expression by NGF. In the past few years it has become clear that decreased amounts of NGF at the level of BFCN cell bodies is largely due to failed retrograde transport rather than decreased synthesis, binding or expression of NGF receptors in the BFCN terminals. We will discuss in vivo evidence supporting decreased retrograde transport of NGF in a mouse model with BFCN degeneration, and will attempt to match these findings with our studies in postmortem human AD brain. We will speculate about the possible mechanisms of failed NGF retrograde transport and its relationship to AD pathology. | Alzheimer’s disease and NGF signaling |
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0.4926934838294983, "26986": 0.11343330889940262, "27011": 0.29255300760269165, "27065": 0.22548456490039825, "27197": 0.9470623731613159, "27312": 0.5718178153038025, "27351": 0.22937409579753876, "28141": 0.37640097737312317, "28329": 0.3339579105377197, "28436": 0.13071982562541962, "28697": 0.24631060659885406, "28879": 0.11951763927936554, "29295": 0.009718249551951885, "29299": 0.5865923762321472, "29458": 0.10993985831737518} | 24660385 | To determine the accuracy of echocardiographic left ventricular (LV) dimension and mass measurements for detection and quantification of LV hypertrophy, results of blindly read antemortem echocardiograms were compared with LV mass measurements made at necropsy in 55 patients. LV mass was calculated using M-mode LV measurements by Penn and American Society of Echocardiography (ASE) conventions and cube function and volume correction formulas in 52 patients. Penn-cube LV mass correlated closely with necropsy LV mass (r = 0.92, p less than 0.001) and overestimated it by only 6%; sensitivity in 18 patients with LV hypertrophy (necropsy LV mass more than 215 g) was 100% (18 of 18 patients) and specificity was 86% (29 of 34 patients). ASE-cube LV mass correlated similarly to necropsy LV mass (r = 0.90, p less than 0.001), but systematically overestimated it (by a mean of 25%); the overestimation could be corrected by the equation: LV mass = 0.80 (ASE-cube LV mass) + 0.6 g. Use of ASE measurements in the volume correction formula systematically underestimated necropsy LV mass (by a mean of 30%). In a subset of 9 patients, 3 of whom had technically inadequate M-mode echocardiograms, 2-dimensional echocardiographic (echo) LV mass by 2 methods was also significantly related to necropsy LV mass (r = 0.68, p less than 0.05 and r = 0.82, p less than 0.01). Among other indexes of LV anatomy, only measurement of myocardial cross-sectional area was acceptably accurate for quantitation of LV mass (r = 0.80, p less than 0.001) or diagnosis of LV hypertrophy (sensitivity = 72%, specificity = 94%).(ABSTRACT TRUNCATED AT 250 WORDS) | Echocardiographic assessment of left ventricular hypertrophy: comparison to necropsy findings. |
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0.5893046259880066, "28156": 0.083342544734478, "28696": 0.1332872211933136, "28788": 0.0174254160374403, "28828": 0.06429435312747955, "28829": 0.5855054259300232, "28873": 0.05786345899105072, "28915": 0.1734936386346817, "28927": 0.25088030099868774, "28938": 0.0058422754518687725, "29235": 0.6435998678207397, "29290": 0.3012613356113434, "29295": 0.02887592278420925, "29489": 0.026976587250828743} | 24670522 | The intracellular Ca(2+) concentration of many nonexcitable cells is regulated by calcium store release and store-operated calcium entry (SOCE). In platelets, STIM1 was recently identified as the main calcium sensor expressed in the endoplasmic reticulum. To evaluate the role of the SOC channel moiety, Orai1, in platelet SOCE, we generated mice expressing a mutated, inactive form of Orai1 in blood cells only (Orai1(R93W)). Platelets expressing Orai1(R93W) were characterized by markedly reduced SOCE and impaired agonist-induced increases in [Ca(2+)](i). Orai1(R93W) platelets showed reduced integrin activation and impaired degranulation when stimulated with low agonist concentrations under static conditions. This defect, however, did not significantly affect the ability of Orai1(R93W) platelets to aggregate or to adhere to collagen under arterial flow conditions ex vivo. In contrast, these adherent Orai1(R93W) platelets were defective in surface phosphatidylserine exposure, suggesting that Orai1 is crucial for the platelets' procoagulant response rather than for other Ca(2+)-dependent cellular responses. | R93W mutation in Orai1 causes impaired calcium influx in platelets. |
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0.15023678541183472, "28121": 0.1064341589808464, "28225": 0.1602703034877777, "29147": 0.10203468054533005, "29234": 0.36967599391937256, "29398": 0.0174254160374403, "29477": 0.07159364968538284} | 24697979 | OBJECTIVE To observe the effects on post-stroke depression treated with acupuncture at the acu points based on ziwuliuzhu (the midnight-noon ebb-flow theory). METHODS Ninety-three patients were randomized into a comprehensive group, a ziwuliuzhu group and a prozac group, 31 cases in each group. In the ziwuliuzhu group, acupuncture was applied to the acupoints based on ziwuliuzhu, once a day, 5 times in a week. In the prozac group, fluoxertine hydrochloride (prozac) was prescribed for oral administration, once a day, 20 mg each time. In the comprehensive group, acupuncture based on ziwuliuzhu combined with the oral administration of prozac were adopted and the treatment frequency was the same as the ziwuliuzhu group and the prozac group. The 4-week treatment was taken as one session in the three groups and 6 sessions were required totally. The clinical efficacy and the Hamilton depression rating scale (HAMD) score and the adverse reaction were compared among the 3 groups. RESULTS The total effective rate was 96.8% (30/31) in the comprehensive group, better than 83.9% (26/31) in the ziwuliuzhu group and 80. 6% (25/31) in the prozac group (both P<0.05). In 4, 12 and 24 weeks of treatment, HAMD score was lower significantly than that before the treatment in the three groups (all P<0.05), and the score in the comprehensive group at each time point after treatment was lower than the other two groups (all P<0.05). In 4 and 12 weeks of treatment, there were not different significantly between the ziwuliuzhu group and the prozac group (both P>0.05). In 24 weeks of treatment, HAMD score in the ziwuliuzhu group was lower than that in the prozac group (P<0.05). For the adverse reaction, there were 2 cases in the comprehensive group, 6 cases in the prozac group and 0 case in the ziwzuliuzhu group. CONCLUSION The comprehensive therapy of acupuncture at the acupoints based on ziwuliuzhu and oral administration of prozac is superior to either the simple oral administration of prozac or the ziwuliuzhu acu-puncture in terms of clinical efficacy and the improvements in depressive state. Regarding the clinical efficacy, the impact of simple ziwuliuzhu acupuncture is not different significantly as compared with the simple oral administration of prozac, but it is better than the simple oral administration of prozac in terms of the long-term HAMD score and safety. | [Efficacy on post-stroke depression treated with acupuncture at the acupoints based on ziwuliuzhu and prozac]. |
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"28389": 0.9240728616714478, "28667": 0.38374659419059753, "29251": 0.3177432417869568, "29336": 0.07250232994556427, "29361": 0.012615402229130268, "29566": 0.5838727951049805, "29569": 0.03360854089260101} | 24700152 | Injection drug users (IDUs) are at increased risk for HIV, viral hepatitis, and tuberculosis, and making up more than a quarter of the incarcerated population in the United States. Methadone maintenance treatment of opiate addiction is highly effective at reducing drug use, drug-related criminal activity, and risk of HIV transmission. Recently released inmates are at particularly high risk for overdose and disease transmission. Linkage to methadone treatment immediately upon release from incarceration is a promising opportunity to combat disease transmission, facilitate reentry into the community, and reduce recidivism. | Linkage with methadone treatment upon release from incarceration: a promising opportunity. |
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"28400": 0.03360854089260101, "28648": 0.06429435312747955, "29021": 0.0317181795835495, "29048": 0.5773153901100159, "29361": 0.25088030099868774, "29391": 0.1913948506116867, "29477": 0.7163142561912537} | 24704139 | OBJECTIVE The Diabetes Prevention Program (DPP) is a 27-center randomized clinical trial designed to evaluate the safety and efficacy of interventions that may delay or prevent development of diabetes in people at increased risk for type 2 diabetes. RESEARCH DESIGN AND METHODS Eligibility requirements were age > or = 25 years, BMI > or = 24 kg/m2 (> or = 22 kg/m2 for Asian-Americans), and impaired glucose tolerance plus a fasting plasma glucose of 5.3-6.9 mmol/l (or < or = 6.9 mmol for American Indians). Randomization of participants into the DPP over 2.7 years ended in June 1999. Baseline data for the three treatment groups--intensive lifestyle modification, standard care plus metformin, and standard care plus placebo--are presented for the 3,234 participants who have been randomized. RESULTS Of all participants , 55% were Caucasian, 20% were African-American, 16% were Hispanic, 5% were American Indian, and 4% were Asian-American. Their average age at entry was 51 +/- 10.7 years (mean +/- SD), and 67.7% were women. Moreover, 16% were < 40 years of age, and 20% were > or = 60 years of age. Of the women, 48% were postmenopausal. Men and women had similar frequencies of history of hypercholesterolemia (37 and 33%, respectively) or hypertension (29 and 26%, respectively). On the basis of fasting lipid determinations, 54% of men and 40% of women fit National Cholesterol Education Program criteria for abnormal lipid profiles. More men than women were current or former cigarette smokers or had a history of coronary heart disease. Furthermore, 66% of men and 71% of women had a first-degree relative with diabetes. Overall, BMI averaged 34.0 +/- 6.7 kg/m2 at baseline with 57% of the men and 73% of women having a BMI > or = 30 kg/m2. Average fasting plasma glucose (6.0 +/- 0.5 mmol/l) and HbA1c (5.9 +/- 0.5%) in men were comparable with values in women (5.9 +/- 0.4 mmol/l and 5.9 +/- 0.5%, respectively). CONCLUSIONS The DPP has successfully randomized a large cohort of participants with a wide distribution of age, obesity, and ethnic and racial backgrounds who are at high risk for developing type 2 diabetes. The study will examine the effects of interventions on the development of diabetes. | The Diabetes Prevention Program: baseline characteristics of the randomized cohort. The Diabetes Prevention Program Research Group. |
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0.4132472574710846} | 24705390 | BACKGROUND & AIMS Helicobacter pylori is an important etiologic factor in the development of gastric cancer. The aim of this study was to analyze the role of H. pylori infections in the induction of mutagenic events in gastric epithelial cells. The effect of a high-salt diet as a genotoxic risk factor was also investigated. METHODS Big Blue transgenic male mice (C57Bl/6) were inoculated with H. pylori (strain SS1) or Helicobacter felis (strain CS1) for 6 and 12 months. The frequency and spectrum of mutations at the stomach level were assessed. Inflammatory host response and inducible nitric oxide synthase (iNOS) expression by reverse-transcription polymerase chain reaction and immunohistochemistry analysis were also performed. RESULTS After 6 months, the gastric mutant frequency was 4-fold and 1.7-fold higher in mice infected with H. pylori and H. felis, respectively, than in uninfected mice. It was associated with a high frequency of transversions (AT --> CG and GC --> TA) known to result from oxidative damages. The Helicobacter-infected mice exhibited severe gastritis and a high level of iNOS messenger RNA expression. Hyperplasia developed 12 months after inoculation, and both the mutagenic effects and iNOS expression decreased in H. pylori- and H. felis-infected mice. No synergistic effects of a high-salt diet and Helicobacter infection were observed regarding the frequency of gastric mutation. CONCLUSIONS A direct gastric mutagenic effect due to H. pylori infection in the Big Blue transgenic mouse model has been shown 6 months after inoculation. This genotoxicity can be attributable to oxidative DNA damage involving the inflammatory host response. | Chronic Helicobacter pylori infections induce gastric mutations in mice. |
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0.025073638185858727, "26591": 0.1332872211933136, "26835": 0.0770333781838417, "27006": 0.1221139207482338, "27116": 0.0842406153678894, "27441": 1.0748957395553589, "27777": 0.09228714555501938, "27854": 0.08782484382390976, "27989": 0.5816917419433594, "28117": 0.613389253616333, "28406": 0.2822965085506439, "28691": 0.1229778528213501, "28873": 0.036437395960092545, "29354": 0.1011524572968483, "29533": 0.20580662786960602} | 24706198 | The Tat system transports folded proteins across bacterial and thylakoid membranes. In Gram-negative organisms, a TatABC substrate-binding complex and separate TatA complex are believed to coalesce to form an active translocon, with all three subunits essential for translocation. Most Gram-positive organisms lack a tatB gene, indicating major differences in organization and possible differences in mode of action. Here, we have studied Tat complexes encoded by the tatAdCd genes of Bacillus subtilis. Expression of tatAdCd in an Escherichia coli tat null mutant results in efficient export of a large, cofactor-containing E. coli Tat substrate, TorA. We show that the tatAd gene complements E. coli mutants lacking either tatAE or tatB, indicating a bifunctional role for this subunit in B. subtilis. Second, we have identified and characterized two distinct Tat complexes that are novel in key respects: a TatAdCd complex of approximately 230 kDa that is significantly smaller than the analogous E. coli TatABC complex (approximately 370 kDa on BN gels) and a separate TatAd complex. The latter is a discrete entity of approximately 270 kDa as judged by gel filtration chromatography, very different from the highly heterogeneous E. coli TatA complex that ranges in size from approximately 50 kDa to over 600 kDa. TatA heterogeneity has been linked to the varying size of Tat substrates being translocated, but the singular nature of the B. subtilis TatAd complex suggests that discrete TatAC and TatA complexes may form a single form of translocon. | A minimal Tat system from a gram-positive organism: a bifunctional TatA subunit participates in discrete TatAC and TatA complexes. |
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0.46670228242874146, "29295": 0.06977381557226181} | 24707550 | Macrophages play a pivotal role in innate and acquired immune responses to Schistosoma mansoni. Classical (M1) or alternative (M2) activation states of these cells further delineate their roles in tissue damage through innate immunity or fibrotic remodeling, respectively. In the present study, we addressed the following question: Does systemic Th2-type cytokine polarization evoked by S. mansoni affect macrophage differentiation and activation? To this end, we analyzed bone marrow-derived macrophages from mice with S. mansoni egg-induced pulmonary granulomas and unchallenged (or naïve) mice to determine their activation state and their response to specific TLR agonists, including S. mansoni egg antigens. Unlike naïve macrophages, macrophages from Th2-polarized mice constitutively expressed significantly higher "found in inflammatory zone-1" (FIZZ1) and ST2 (M2 markers) and significantly lower NO synthase 2, CCL3, MIP-2, TNF-alpha, and IL-12 (M1 markers). Also, compared with naïve macrophages, Th2-polarized macrophages exhibited enhanced responses to the presence of specific TLR agonists, which consistently induced significantly higher levels of gene and protein levels for M2 and M1 markers in these cells. Together, these data show that signals received by bone marrow precursors during S. mansoni egg-induced granuloma responses dynamically alter the development of macrophages and enhance the TLR responsiveness of these cells, which may ultimately have a significant effect on the pulmonary granulomatous response. | A systemic granulomatous response to Schistosoma mansoni eggs alters responsiveness of bone-marrow-derived macrophages to Toll-like receptor agonists. |
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"26402": 1.039613962173462, "26524": 0.045809537172317505, "26773": 0.06429435312747955, "26953": 1.2392796277999878, "27054": 0.055094651877880096, "27084": 1.3201920986175537, "27200": 0.018384648486971855, "27208": 0.19541899859905243, "27295": 0.0009760859538801014, "27781": 0.004870930220931768, "27854": 0.36697331070899963, "28086": 1.076228141784668, "28155": 0.20102575421333313, "28156": 0.23710809648036957, "28329": 0.755608320236206, "28667": 0.613389253616333, "28728": 0.020300358533859253} | 24712186 | The two membrane proteins, STIM1 and Orai1, have each been shown to be essential for the activation of store-operated channels (SOC). Yet, how these proteins functionally interact is not known. Here, we reveal that STIM1 and Orai1 expressed together reconstitute functional SOCs. Expressed alone, Orai1 strongly reduces store-operated Ca(2+) entry (SOCE) in human embryonic kidney 293 cells and the Ca(2+) release-activated Ca(2+) current (I(CRAC)) in rat basophilic leukemia cells. However, expressed along with the store-sensing STIM1 protein, Orai1 causes a massive increase in SOCE, enhancing the rate of Ca(2+)entry by up to 103-fold. This entry is entirely store-dependent since the same coexpression causes no measurable store-independent Ca(2+) entry. The entry is completely blocked by the SOC blocker, 2-aminoethoxydiphenylborate. Orai1 and STIM1 coexpression also caused a large gain in CRAC channel function in rat basophilic leukemia cells. The close STIM1 homologue, STIM2, inhibited SOCE when expressed alone but coexpressed with Orai1 caused substantial constitutive (store-independent) Ca(2+) entry. STIM proteins are known to mediate Ca(2+) store-sensing and endoplasmic reticulum-plasma membrane coupling with no intrinsic channel properties. Our results revealing a powerful gain in SOC function dependent on the presence of both Orai1 and STIM1 strongly suggest that Orai1 contributes the PM channel component responsible for Ca(2+) entry. The suppression of SOC function by Orai1 overexpression likely reflects a required stoichiometry between STIM1 and Orai1. | Orai1 and STIM reconstitute store-operated calcium channel function. |
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Here, we derive mouse embryonic fibroblasts (MEFs) deleted in all three Tet genes and examine their capacity for reprogramming into induced pluripotent stem cells (iPSCs). We show that Tet-deficient MEFs cannot be reprogrammed because of a block in the mesenchymal-to-epithelial transition (MET) step. Reprogramming of MEFs deficient in TDG is similarly impaired. The block in reprogramming is caused at least in part by defective activation of key miRNAs, which depends on oxidative demethylation promoted by Tet and TDG. Reintroduction of either the affected miRNAs or catalytically active Tet and TDG restores reprogramming in the knockout MEFs. Thus, oxidative demethylation to promote gene activation appears to be functionally required for reprogramming of fibroblasts to pluripotency. These findings provide mechanistic insight into the role of epigenetic barriers in cell-lineage conversion. | Tet and TDG mediate DNA demethylation essential for mesenchymal-to-epithelial transition in somatic cell reprogramming. |
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"26846": 0.9827804565429688, "26909": 0.19782574474811554, "27095": 0.06429435312747955, "27179": 0.535327672958374, "27338": 0.14686977863311768, "27348": 1.0108904838562012, "27564": 0.14939609169960022, "28031": 0.009718249551951885, "28032": 0.2026219218969345, "28296": 0.9500881433486938, "28436": 0.37640097737312317, "28775": 0.8500841856002808, "28873": 0.46363574266433716, "28896": 0.6128603219985962, "28935": 1.2948341369628906, "28943": 0.23556606471538544, "29392": 0.14518201351165771, "29438": 0.10993985831737518, "29458": 0.5145297050476074} | 24721347 | The founding fathers of malariology combined scientific originality, perseverance in research, strong characters, breadth of interest and social concern. A hundred years later research and understanding has made immense progress but the world still bears a huge burden of malaria. For the next century research requires both more specialism and a holistic range if it is to be used in control, requiring multidisciplinary team work. Environmental changes and interventions produce a dynamic and changing pattern of malaria, not the static one of the past. From the original parasite life cycle, research has analysed a series of other cycles at electron microscope, biochemical and genome levels on decreasing size scales and quantitative epidemiological cycles for control. Recent additions to these concepts have been stage-specific antigens, cycles of disease rather than parasites alone, considering populations of parasites rather than just cases, and also genetic variation in each component of the parasite-human host-vector triad. In this volume there emerges for the first time a coherent overall picture of the biomedical aspects of basic malariology as the interacting population genetics of malaria parasites, anophelines and people. This provides a coherent model for the new century dealing with the great biological malaria problems of drug resistance, vaccine development, insecticidal and net control and can feed, with socio-economic work, into the gathering renewal of control efforts. New work on large-scale changes of malaria in space and time enables us to be precise about effects of local and global environmental changes to predict epidemics. Future research will be as much about linking these different scales of understanding as control will be about linking different levels of the health system. The grim situation in poor holoendemic countries also requires practical support of the type that the founders of malariology were involved in. A coherent understanding needs to feed into the new control efforts, from Roll Back Malaria onwards, for the next century. | The last and the next hundred years of malariology. |
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"27321": 0.554580807685852, "27356": 0.016465263441205025, "27531": 0.1229778528213501, "27605": 0.6202403903007507, "27814": 0.3070250153541565, "27833": 0.24325250089168549, "27854": 0.15693697333335876, "28173": 0.35403475165367126, "28516": 0.09495500475168228, "28788": 0.12642613053321838, "28848": 0.00875066313892603, "28976": 0.07068414986133575, "29166": 0.8925741910934448, "29290": 0.6492279767990112, "29441": 0.036437395960092545, "29490": 0.10467668622732162} | 24721866 | Macrophage-derived foam cells play important roles in the progression of atherosclerosis. We reported previously that ERK1/2-dependent granulocyte/macrophage colony-stimulating factor (GM-CSF) expression, leading to p38 MAPK/ Akt signaling, is important for oxidized low density lipoprotein (Ox-LDL)-induced macrophage proliferation. Here, we investigated whether activation of AMP-activated protein kinase (AMPK) could suppress macrophage proliferation. Ox-LDL-induced proliferation of mouse peritoneal macrophages was assessed by [(3)H]thymidine incorporation and cell counting assays. The proliferation was significantly inhibited by the AMPK activator 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR) and restored by dominant-negative AMPKalpha1, suggesting that AMPK activation suppressed macrophage proliferation. AICAR partially suppressed Ox-LDL-induced ERK1/2 phosphorylation and GM-CSF expression, suggesting that another mechanism is also involved in the AICAR-mediated suppression of macrophage proliferation. AICAR suppressed GM-CSF-induced macrophage proliferation without suppressing p38 MAPK/Akt signaling. GM-CSF suppressed p53 phosphorylation and expression and induced Rb phosphorylation. Overexpression of p53 or p27(kip) suppressed GM-CSF-induced macrophage proliferation. AICAR induced cell cycle arrest, increased p53 phosphorylation and expression, and suppressed GM-CSF-induced Rb phosphorylation via AMPK activation. Moreover, AICAR induced p21(cip) and p27(kip) expression via AMPK activation, and small interfering RNA (siRNA) of p21(cip) and p27(kip) restored AICAR-mediated suppression of macrophage proliferation. In conclusion, AMPK activation suppressed Ox-LDL-induced macrophage proliferation by suppressing GM-CSF expression and inducing cell cycle arrest. These effects of AMPK activation may represent therapeutic targets for atherosclerosis. | Activation of AMP-activated protein kinase suppresses oxidized low-density lipoprotein-induced macrophage proliferation. |
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"26163": 0.2317005842924118, "26189": 0.272677481174469, "26419": 1.0695481300354004, "26535": 0.23247487843036652, "26637": 0.6280876994132996, "26786": 0.3423145115375519, "26819": 0.11778303235769272, "26876": 0.6764062643051147, "27011": 0.6970458030700684, "27058": 1.2204381227493286, "27144": 0.0009760859538801014, "27159": 0.48850810527801514, "27197": 0.987156867980957, "27312": 0.36086538434028625, "27323": 0.3601844012737274, "27404": 0.3656192123889923, "27528": 0.3615458607673645, "27718": 0.23864774405956268, "27725": 0.45994341373443604, "28228": 1.070887804031372, "28436": 0.040196798741817474, "28472": 0.1064341589808464, "28696": 0.11778303235769272, "28929": 1.2324692010879517, "28940": 0.007782140281051397, "29130": 0.09406650811433792, "29278": 0.4450363218784332, "29333": 0.46853771805763245} | 24724242 | BACKGROUND The absolute risk of fractures in renal transplant patients is 3 times that of matched controls. Most of the symptomatic fractures are peripheral, suggesting a greater compromise of cortical bone. Peripheral quantitative computed tomography (pQCT) is a new imaging technique that allows separate noninvasive evaluations of cortical and trabecular bones. We investigated cortical bone by pQCT in 12 renal transplant patients (seven men and five women) for comparison with 27 normal controls. METHODS pQCT (XCT 960, Stratec, Pforheim, Germany) was performed upon the distal radius of the nondominant forearm (15% the length of the ulna, proximal from the radius end plate). We evaluated total and cortical bone mineral density (TBMD, cBMD), total (cross-sectional) and cortical area (TA, cA), cortical thickness (cThk), endosteal and periosteal circumferences, and the buckling ratio (r/cThK). RESULTS Compared with normal controls transplant patients as a whole showed a significant increase in TA, in endosteal circumference (P < .001), and in the buckling ratio (P < .001) with a significant reduction in cThK (P < .001). Female patients had a marked decrease in cA (51.4 vs 69.3 [pixel n]; P < .0001) and cThK (2.08 vs 2.78 mm; P < .0001). Male patients also had a decrease in cThK (2.54 vs 3.30 mm; P = .0001) and an increase in endosteal perimeter (31.2 vs 26.4 mm; P < .0001). Total time on dialysis prior to renal graft correlated negatively with cortical thickness (r = .62; P < .01). CONCLUSIONS Our results suggest that a marked thinning of cortical bone may explain the increased incidence of peripheral fractures among renal transplant patients. | Evaluation of cortical bone by peripheral quantitative computed tomography in renal transplant recipients. |
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METHODS We performed whole-exome sequencing in a patient with ataxia and hypogonadotropic hypogonadism, followed by targeted sequencing of candidate genes in similarly affected patients. Neurologic and reproductive endocrine phenotypes were characterized in detail. The effects of sequence variants and the presence of an epistatic interaction were tested in a zebrafish model. RESULTS Digenic homozygous mutations in RNF216 and OTUD4, which encode a ubiquitin E3 ligase and a deubiquitinase, respectively, were found in three affected siblings in a consanguineous family. Additional screening identified compound heterozygous truncating mutations in RNF216 in an unrelated patient and single heterozygous deleterious mutations in four other patients. Knockdown of rnf216 or otud4 in zebrafish embryos induced defects in the eye, optic tectum, and cerebellum; combinatorial suppression of both genes exacerbated these phenotypes, which were rescued by nonmutant, but not mutant, human RNF216 or OTUD4 messenger RNA. All patients had progressive ataxia and dementia. Neuronal loss was observed in cerebellar pathways and the hippocampus; surviving hippocampal neurons contained ubiquitin-immunoreactive intranuclear inclusions. Defects were detected at the hypothalamic and pituitary levels of the reproductive endocrine axis. CONCLUSIONS The syndrome of hypogonadotropic hypogonadism, ataxia, and dementia can be caused by inactivating mutations in RNF216 or by the combination of mutations in RNF216 and OTUD4. These findings link disordered ubiquitination to neurodegeneration and reproductive dysfunction and highlight the power of whole-exome sequencing in combination with functional studies to unveil genetic interactions that cause disease. (Funded by the National Institutes of Health and others.). | Ataxia, dementia, and hypogonadotropism caused by disordered ubiquitination. |
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"25468": 0.48068851232528687, "25634": 0.7248653769493103, "25778": 0.2184450328350067, "26399": 0.9576126337051392, "26402": 0.2089812457561493, "26520": 1.2210142612457275, "26651": 0.27786844968795776, "27144": 0.817850649356842, "27226": 0.026976587250828743, "27321": 0.09317722171545029, "27777": 0.01934296265244484, "27781": 0.3325583338737488, "27881": 0.40351006388664246, "27895": 0.5984715819358826, "28207": 0.16690383851528168, "28285": 0.2231435477733612, "28295": 0.18411032855510712, "28467": 0.6075552701950073, "28591": 0.33675122261047363, "28696": 0.2983669638633728, "28788": 0.8699195384979248, "28873": 0.9724938273429871, "28896": 0.3963087201118469, "29290": 0.3723714053630829} | 24726600 | Evidence suggests that cancer immunotherapy will be a major part of the combination treatment plan for many patients with many cancer types in the near future. There are many types of immune processes involving different antitumour and tumour-promoting leucocytes, and tumour cells use many strategies to evade the immune response. The tumour microenvironment can help determine which immune suppressive pathways become activated to restrain antitumour immunity. This includes immune checkpoint receptors on effector T-cells and myeloid cells, and release of inhibitory cytokines and metabolites. Therapeutic approaches that target these pathways, particularly immune-checkpoint receptors, can induce durable antitumour responses in patients with advanced-stage cancers, including melanoma. Nevertheless, many patients do not have a good response to monotherapy approaches and alternative strategies are required to achieve optimal therapeutic benefit. These strategies include eliminating the bulk of tumour cells to provoke tumour-antigen release and antigen-presenting cell (APC) function, using adjuvants to enhance APC function, and using agents that enhance effector-cell activity. In this Review, we discuss the stratification of the tumour microenvironment according to tumour-infiltrating lymphocytes and PD-L1 expression in the tumour, and how this stratification enables the design of optimal combination cancer therapies tailored to target different tumour microenvironments. | Combination cancer immunotherapies tailored to the tumour microenvironment |
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0.255429208278656} | 24730100 | Although it is well established that cAMP inhibits platelet activation induced by all agonists, the thromboxane A(2) signal transduction pathway was found to be particularly sensitive to such inhibition. Therefore, we examined whether cAMP-dependent kinase mediates phosphorylation of the thromboxane A(2) receptor-G-protein complex. It was found that cAMP induces protein kinase A-dependent [gamma-(32)P]ATP labeling of solubilized membrane proteins in the region of Galpha subunits, i.e. 38-45 kDa. Moreover, ligand affinity chromatography purification of thromboxane A(2) receptor-G-protein complexes from these membranes revealed that 38-45-kDa phosphoproteins co-purify with thromboxane A(2) receptors. Immunoprecipitation of the affinity column eluate with a Galpha(13) antibody demonstrated that 8-Br-cAMP increased phosphorylation of thromboxane A(2) receptor-associated Galpha(13) by 87 +/- 27%. In separate experiments, immunopurification of Galpha(13) on microtiter wells coated with a different Galpha(13) antibody revealed that 8-Br-cAMP increased Galpha(13) phosphorylation by 53 +/- 19%. Finally, treatment of (32)P-labeled whole platelets with prostacyclin resulted in a 90 +/- 14% increase in phosphorylated Galpha(13) that was abolished by pretreatment with the adenylate cyclase inhibitor MDL-12. These results provide the first evidence that protein kinase A mediates phosphorylation of Galpha(13) both in vitro and in vivo and provides a basis for the preferential inhibition of thromboxane A(2)-mediated signaling in platelets by cAMP. | Cyclic AMP-dependent phosphorylation of thromboxane A(2) receptor-associated Galpha(13). |
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0.7163142561912537} | 24731248 | 5-methylcytosine (5mC) in DNA plays an important role in gene expression, genomic imprinting, and suppression of transposable elements. 5mC can be converted to 5-hydroxymethylcytosine (5hmC) by the Tet (ten eleven translocation) proteins. Here, we show that, in addition to 5hmC, the Tet proteins can generate 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC) from 5mC in an enzymatic activity-dependent manner. Furthermore, we reveal the presence of 5fC and 5caC in genomic DNA of mouse embryonic stem cells and mouse organs. The genomic content of 5hmC, 5fC, and 5caC can be increased or reduced through overexpression or depletion of Tet proteins. Thus, we identify two previously unknown cytosine derivatives in genomic DNA as the products of Tet proteins. Our study raises the possibility that DNA demethylation may occur through Tet-catalyzed oxidation followed by decarboxylation. | Tet proteins can convert 5-methylcytosine to 5-formylcytosine and 5-carboxylcytosine. |
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"28794": 0.11517547070980072, "29361": 0.00875066313892603} | 24735908 | CONTEXT Aspirin is widely used for relief of pain and for cardioprotective effects. Its use is of concern to ophthalmologists when ocular surgery is being considered and also in the presence of age-related macular degeneration (AMD). OBJECTIVE To examine the association of regular aspirin use with incidence of AMD. DESIGN, SETTING, AND PARTICIPANTS The Beaver Dam Eye Study, a longitudinal population-based study of age-related eye diseases conducted in Wisconsin. Examinations were performed every 5 years over a 20-year period (1988-1990 through 2008-2010). Study participants (N = 4926) were aged 43 to 86 years at the baseline examination. At subsequent examinations, participants were asked if they had regularly used aspirin at least twice a week for more than 3 months. MAIN OUTCOME MEASURE Incidence of early AMD, late AMD, and 2 subtypes of late AMD (neovascular AMD and pure geographic atrophy), assessed in retinal photographs according to the Wisconsin Age-Related Maculopathy Grading System. RESULTS The mean duration of follow-up was 14.8 years. There were 512 incident cases of early AMD (of 6243 person-visits at risk) and 117 incident cases of late AMD (of 8621 person-visits at risk) over the course of the study. Regular aspirin use 10 years prior to retinal examination was associated with late AMD (hazard ratio [HR], 1.63 [95% CI, 1.01-2.63]; P = .05), with estimated incidence of 1.76% (95% CI, 1.17%-2.64%) in regular users and 1.03% (95% CI, 0.70%-1.51%) in nonusers. For subtypes of late AMD, regular aspirin use 10 years prior to retinal examination was significantly associated with neovascular AMD (HR, 2.20 [95% CI, 1.20-4.15]; P = .01) but not pure geographic atrophy (HR, 0.66 [95% CI, 0.25-1.95]; P = .45). Aspirin use 5 years (HR, 0.86 [95% CI, 0.71-1.05]; P = .13) or 10 years (HR, 0.86 [95% CI, 0.65-1.13]; P = .28) prior to retinal examination was not associated with incident early AMD. CONCLUSIONS Among an adult cohort, aspirin use 5 years prior to observed incidence was not associated with incident early or late AMD. However, regular aspirin use 10 years prior was associated with a small but statistically significant increase in the risk of incident late and neovascular AMD. | Long-term use of aspirin and age-related macular degeneration. |
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0.07068414986133575, "28290": 0.00875066313892603, "28450": 0.03266380727291107, "28687": 0.022212404757738113, "28689": 0.2317005842924118, "28828": 0.2607102394104004, "28829": 0.33675122261047363, "28927": 0.18816383183002472, "29172": 0.06612417846918106, "29206": 0.8973627090454102, "29458": 0.06703783571720123, "29516": 0.10026945173740387} | 24737389 | Ribosome biogenesis and protein synthesis are two of the most energy consuming processes in a growing cell. Moreover, defects in their molecular components can alter the pattern of gene expression. Thus it is understandable that cells have developed a surveillance system to monitor the status of the translational machinery. Recent discoveries of causative mutations and deletions in genes linked to ribosome biogenesis have defined a group of similar pathologies termed ribosomopathies. Over the past decade, much has been learned regarding the relationship between growth control and ribosome biogenesis. The discovery of extra-ribosomal functions of several ribosome proteins and their regulation of p53 levels has provided a link from ribosome impairment to cell cycle regulation. Yet, evidence suggesting p53 and/or Hdm2 independent pathways also exists. In this review, we summarize recent advances in understanding the mechanisms underlying the pathologies of ribosomopathies and discuss the relationship between ribosome production and tumorigenesis. | Growth control and ribosomopathies. |
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(TF) activation. We explored how TFs process signaling inputs to generate diverse dynamic responses. The budding yeast general stress-responsive TF Msn2 acted as a tunable signal processor that could track, filter, or integrate signals in an input-dependent manner. This tunable signal processing appears to originate from dual regulation of both nuclear import and export by phosphorylation, as mutants with one form of regulation sustained only one signal-processing function. Versatile signal processing by Msn2 is crucial for generating distinct dynamic responses to different natural stresses. Our findings reveal how complex signal-processing functions are integrated into a single molecule and provide a guide for the design of TFs with "programmable" signal-processing functions. | Tunable signal processing through modular control of transcription factor translocation. |
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respective targets. This traditional view has been challenged by studies that propose an alternative, unified mechanism of killing, whereby toxic reactive oxygen species (ROS) are produced in the presence of antibiotics. We found no correlation between an individual cell's probability of survival in the presence of antibiotic and its level of ROS. An ROS quencher, thiourea, protected cells from antibiotics present at low concentrations, but the effect was observed under anaerobic conditions as well. There was essentially no difference in survival of bacteria treated with various antibiotics under aerobic or anaerobic conditions. This suggests that ROS do not play a role in killing of bacterial pathogens by antibiotics. | Killing by bactericidal antibiotics does not depend on reactive oxygen species. |
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1.2959036827087402, "26305": 0.28082266449928284, "26383": 0.13157635927200317, "26396": 0.6629094481468201, "26557": 0.7692760229110718, "26601": 0.2447827309370041, "26651": 0.2954642176628113, "26741": 0.07250232994556427, "27011": 0.151916041970253, "27179": 0.3464667797088623, "27480": 1.0986123085021973, "27989": 0.10731173306703568, "28156": 0.7389566898345947, "28228": 0.7153595685958862, "28290": 1.126855492591858, "28685": 0.28450319170951843, "28688": 0.680370569229126, "28828": 0.4770587682723999, "28829": 0.3034266233444214, "28976": 0.45623743534088135, "29105": 0.6543170213699341, "29292": 0.04487626627087593, "29349": 0.0029254043474793434} | 24760136 | PURPOSE To describe a naturally occurring X-linked recessive mutation, no b-wave (nob), that compromises visual transmission between photoreceptors and second-order neurons in mice. METHODS Affected mice were identified by recording the light-evoked response of the retina, the electroretinogram (ERG). To evaluate visual transmission, cortical potentials were recorded with a scalp electrode. The inheritance pattern for nob was defined by breeding nob animals with normal mice. Retinal histologic analysis was performed by light microscopy. RESULTS Although the photoreceptor-mediated ERG component (a-wave) was normal in nob mice, the major response component reflecting postreceptoral neuronal activity (b-wave) was missing. Visually-driven cortical activity was also abnormal in nob animals. At the light microscopic level, the nob retina appeared to have a normal cytoarchitecture. CONCLUSIONS These findings suggest that the nob defect interferes with the transmission of visual information through the retina and that these mice are a useful model for the study of outer retinal synaptic function. In addition, this mutant mouse seems to provide an animal model for the complete form of congenital stationary night blindness, a human disorder in which patients have a profound loss of rod-mediated visual sensitivity. | A naturally occurring mouse model of X-linked congenital stationary night blindness. |
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0.1930064558982849, "26773": 0.3034266233444214, "27144": 0.13499516248703003, "27343": 0.02887592278420925, "28086": 1.19829261302948, "28227": 0.7389566898345947, "28228": 0.8083226680755615, "28405": 0.15275461971759796, "28788": 0.08244366943836212, "29290": 0.2470736801624298, "29514": 0.8212929964065552, "29610": 0.45623743534088135} | 24766509 | Previously, we have demonstrated that mesenchymal stem cells could be differentiated into steroidogenic cells through steroidogenic factor-1 and 8bromo-cAMP treatment. Use of liver receptor homolog-1, another of the nuclear receptor 5A family nuclear receptors, with 8bromo-cAMP also resulted in the differentiation of human mesenchymal stem cells into steroid hormone-producing cells. The same approaches could not be applied to other undifferentiated cells such as embryonic stem cells or embryonal carcinoma cells, because the over-expression of the nuclear receptor 5A family is cytotoxic to these cells. We established embryonic stem cells carrying tetracycline-regulated steroidogenic factor-1 gene at the ROSA26 locus. The embryonic stem cells were first differentiated into a mesenchymal cell lineage by culturing on collagen IV-coated dishes and treating with pulse exposures of retinoic acid before expression of steroidogenic factor-1. Although the untreated embryonic stem cells could not be converted into steroidogenic cells by expression of steroidogenic factor-1 in the absence of leukemia inhibitory factor due to inability of the cells to survive, the differentiated cells could be successfully converted into steroidogenic cells when expression of steroidogenic factor-1 was induced. They exhibited characteristics of adrenocortical-like cells and produced a large amount of corticosterone. These results indicated that pluripotent stem cells could be differentiated into steroidogenic cells by the nuclear receptor 5A family of protein via the mesenchymal cell lineage. This approach may provide a source of cells for future gene therapy for diseases caused by steroidogenesis deficiencies. | Differentiation of mesenchymal stem cells and embryonic stem cells into steroidogenic cells using steroidogenic factor-1 and liver receptor homolog-1. |
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"26452": 0.06886265426874161, "26456": 1.013020396232605, "26886": 0.012615402229130268, "26928": 0.37640097737312317, "27144": 0.3622259199619293, "27268": 0.8559102416038513, "27484": 0.8433839678764343, "27509": 1.0986123085021973, "27756": 0.24554696679115295, "28064": 0.09938567131757736, "28474": 0.11256109178066254, "28616": 0.21214580535888672, "28965": 0.14686977863311768, "29004": 1.0628231763839722, "29212": 0.03266380727291107, "29299": 0.5261374711990356, "29310": 0.23402166366577148, "29398": 0.10379679501056671} | 24770122 | To assess the clinical and personality characteristics of patients with chronic daily headache before and after treatment, 20 patients were examined and the Minnesota Multiphasic Personality Inventory (MMPI [Italian 356-item abbreviated version]) and the Strait and Trait Anxiety Index 1,2 (STAI) administered. There were two groups: group 1 (n = 6), with a "conversion V" configuration (with elevation of hypochondria and hysteria scales, the depression scale being somewhat lower); and group 2 (n = 13) with elevation of depression and of other MMPI scales. One patient had no scale elevation. STAI 1,2 scores were high in both groups. Several psychosomatic symptoms and some migraine features were present in almost all patients. Occurrence, severity, and duration of headache were recorded regularly and the MMPI and the STAI administered again after treatment. Improvement of headaches and a decrease of several MMPI and STAI 2 scores were observed. However, 12 of 20 patients showed a conversion V configuration after treatment. It is concluded that chronic daily headache was transformed migraine in most cases and was accompanied by anxiety levels in all patients and hysteric traits in some. With time, these patients may develop a depressive disorder. After treatment, hysterical traits are still present at a lower level in those showing these traits before treatment and may be unmasked in those that had depression. | Chronic daily headache. A clinical and psychological profile before and after treatment. |
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(IRKs) are highly K(+)-selective, integral membrane proteins that help maintain resting the membrane potential and cell volume. Integral membrane proteins as a class are frequently N-glycosylated with the attached carbohydrate being extracellular and perhaps modulating function. However, dynamic effects of glycosylation have yet to be demonstrated at the molecular level. ROMK1, a member of the IRK family is particularly suited to the study of glycosylation because it has a single N-glycosylation consensus sequence (Ho, K., Nichols, C. G., Lederer, W. J., Lytton, J., Vassilev, P. M., Kanazirska, M. V., and Herbert, S. C. (1993) Nature 362, 31-38). We show that ROMK1 is expressed in a functional state in the plasmalemma of an insect cell line (Spodoptera frugiperda, Sf9) and has two structures, glycosylated and unglycosylated. To test functionality, glycosylation was abolished by an N117Q mutation or by treatment with tunicamycin. Whole cell currents were greatly reduced in both of the unglycosylated forms compared to wild-type. Single channel currents revealed a dramatic decrease in opening probability, po, as the causative factor. Thus we have shown biochemically that the N-glycosylation sequon is extracellular, a result consistent with present topological models of IRKs, and we conclude that sequon occupancy by carbohydrate stabilizes the open state of ROMK1. | Potassium channel structure and function as reported by a single glycosylation sequon. |
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0.04953393340110779, "28518": 0.32553088665008545, "28848": 0.8400169610977173, "28873": 0.5209306478500366, "29110": 0.11865071207284927, "29299": 0.21530038118362427, "29478": 0.6502478122711182, "29490": 0.25088030099868774} | 24783597 | BACKGROUND Interleukin (IL)-17F, produced in IL-23R-expressing Th17 cells, is a novel member of the IL-17 cytokine family. Given the association of IL23R with inflammatory bowel disease (IBD), we characterized the role of IL-17F in IBD including its intestinal gene expression and the effect of the IL17F p. His161Arg polymorphism on disease susceptibility and phenotype of Crohn's disease (CD) and ulcerative colitis (UC). In addition, we analyzed the IL17F p. His161Arg polymorphism for potential epistasis with IL23R and NOD2/CARD15 variants. METHODS Intestinal IL-17F mRNA expression was measured by quantitative polymerase chain reaction (PCR). Genomic DNA from 1682 individuals (CD: n = 499; UC: n = 216; controls: n = 967) was analyzed for the presence of the IL17F p. His161Arg polymorphism, the 3 NOD2 variants, p. Arg702Trp, p. Gly908Arg, and p. Leu1007fsX1008, and 10 CD-associated IL23R variants. RESULTS Intestinal IL-17F mRNA expression was 4.4-fold increased in inflamed colonic lesions compared to uninflamed biopsies in CD (P = 0.016) but not in UC. However, the mean intestinal IL-17F mRNA expression was higher in UC than in CD (P < 0.0001). The IL17F p. His161Arg substitution was observed with similar frequencies in IBD patients and controls and was not associated with a certain disease phenotype, but weakly associated with a low body mass index (BMI; P = 0.009) and an earlier age of disease onset (P = 0.039) in UC. There was no evidence for epistasis between the IL17F p. His161Arg polymorphism and IBD-associated single nucleotide polymorphisms within the IL23R gene. CONCLUSIONS Intestinal IL17F gene expression is increased in active CD. The IL17F p. His161Arg polymorphism is not associated with IBD susceptibility and has no epistatic interaction with CD-associated IL23R variants. | Role of the novel Th17 cytokine IL-17F in inflammatory bowel disease (IBD): upregulated colonic IL-17F expression in active Crohn's disease and analysis of the IL17F p.His161Arg polymorphism in IBD. |
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The most common variants in the adult and paediatric populations — malignant glioma and medulloblastoma, respectively — have been the subject of increasingly intensive research over the past two decades that has led to considerable advances in the understanding of their basic biology and pathogenesis. This Review summarizes these developments in the context of the evolving notion of molecular pathology and discusses the implications that this work has on the design of new treatment regimens. | Targeting brain cancer: advances in the molecular pathology of malignant glioma and medulloblastoma |
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"27144": 0.42990362644195557, "27159": 0.27342069149017334, "27321": 0.22704219818115234, "27354": 0.0354953333735466, "27453": 0.2247048318386078, "27475": 0.20022670924663544, "27528": 0.0752234235405922, "27544": 0.04394211992621422, "27697": 0.06977381557226181, "27814": 0.2089812457561493, "28086": 0.13925230503082275, "28093": 0.13243216276168823, "28154": 0.11951763927936554, "28196": 0.3084607720375061, "28329": 0.0797421783208847, "28436": 0.1946154683828354, "28667": 0.803087055683136, "28723": 0.9302552938461304, "28739": 0.037378571927547455, "28788": 0.8264343738555908, "28873": 0.16607704758644104, "29251": 0.9021284580230713, "29300": 0.3409265875816345, "29458": 0.9635916948318481, "29494": 0.004870930220931768} | 24795767 | The current study evaluates the role of quantitative measurement of peripheral lymphocyte subsets, especially CD4+ helper T-cell recovery, in predicting transplant outcomes including overall survival (OS) and non-relapse mortality (NRM) after allogeneic stem cell transplantation. A total of 69 allogeneic recipients were included with following diagnoses: acute myeloid leukemia 42, acute lymphoblastic leukemia 5, chronic myeloid leukemia 15, non-Hodgkin's lymphoma 5 and high-risk myelodysplastic syndrome 2. The peripheral lymphocyte subset counts (CD3+ T cells, CD3+4+ helper T cells, CD3+8+ cytotoxic T cells, CD19+ B cells, and CD56+ natural killer cells) were measured at 3, 6 and 12 months. The CD4+ helper T-cell reconstitution at 3 months was strongly correlated with OS (P<0.0001), NRM (P=0.0007), and opportunistic infections (P=0.0108) at the cutoff value of 200 × 106/l CD4+ helper T cells. Rapid CD4+ helper T-cell recovery was also associated with a higher CD4+ helper T-cell transplant dose (P=0.006) and donor type (P<0.001). An early CD4+ helper T-cell recovery at 3 months correlated with a subsequent faster helper T-cell recovery until 12 months, yet not with B-cell recovery. In a multivariate analysis, rapid recovery of CD4+ helper T cells at 3 months was a favorable prognostic factor together with higher CD34+ cell transplant dose in terms of OS (P=0.001) and NRM (P=0.005). | Rapid helper T-cell recovery above 200 × 106/l at 3 months correlates to successful transplant outcomes after allogeneic stem cell transplantation |
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Here we show how a tissue bank from 150 selected homozygous HLA-typed volunteers could match 93% of the UK population with a minimal requirement for immunosuppression. Our model provides a practical approach for using existing HLA-typed samples to generate an iPSC stem cell bank that circumvents prospective typing of a large number of individuals. | Generating an iPSC bank for HLA-matched tissue transplantation based on known donor and recipient HLA types. |
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0.043007105588912964, "28691": 0.10203468054533005, "28774": 0.05970508232712746, "28788": 0.28450319170951843, "28873": 0.9980146884918213, "28964": 0.026025565341114998, "29060": 0.35334911942481995, "29129": 0.6857960224151611, "29206": 0.09406650811433792, "29349": 0.1332872211933136, "29610": 0.5936289429664612} | 24828165 | Thymic epithelial cells (TEC) form the structural and functional microenvironment necessary for the establishment and quality control of the T cell repertoire. In addition, they provide an ectopic source of numerous tissue-restricted antigens (TRA), a feature called promiscuous gene expression (pGE). How the regulation of pGE is related to the cell biology of TEC subset(s), e.g. their turnover and developmental interrelationship is still poorly understood. The observation that pGE is foremost a property of phenotypically and functionally mature medullary TEC (mTEC) implies that the full implementation of pGE is contingent on mTEC differentiation. Here, we show that the emergence of TEC subsets and pGE is tightly correlated during ontogeny and we provide evidence that mature CD80pos mTEC develop from an immature CD80neg subset. This differentiation step proceeds continuously in the postnatal thymus. While mature mTEC turnover in 2 to 3 weeks, immature mTEC encompass a smaller cycling and a larger non-cycling pool. The latter might serve as a reservoir of committed precursors, which sustain this renewal process. Our data document that mTEC represent a highly dynamic cell population, and they imply that the availability and display of TRA in the thymus undergoes a perpetual temporal and spatial reorganization. | Promiscuous gene expression and the developmental dynamics of medullary thymic epithelial cells. |
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0.6270449161529541, "29300": 0.22937409579753876, "29458": 1.1070401668548584, "29490": 0.29619070887565613} | 24834968 | OBJECTIVES The value of HER-2/neu status as a predictor of response to anthracycline-based chemotherapy is still a matter of debate. We evaluated the contribution of HER-2/neu gene amplification and other biologic markers in predicting response to different doses of neoadjuvant anthracycline-based chemotherapy. METHODS Clinical and pathologic records of 115 primary breast cancer patients were reviewed. Forty-eight and 67 patients received high (doxorubicin > or =20 mg/m2/wk; epirubicin > or =30 mg/m2/wk) and moderate-low anthracycline dose intensity regimens, respectively. Pathologic diagnosis, hormonal receptor status (HR), Ki67, and HER-2/neu status were assessed on tumor samples before neoadjuvant chemotherapy. HER-2/neu was determined by fluorescence in situ hybridization (FISH). RESULTS HER-2/neu amplification was observed in 29/115 (25%) tumors, 18 from moderate-low-dose and 11 from high-dose group. In the univariate analysis, a high Ki67 index (> or =20%) and positive clinical axillary nodes were predictive of an objective tumor response (P = 0.033 and 0.001, respectively). In the multivariate analysis, Ki67 was the only factor predictive of response (OR = 3.08, 95% CI = 1.1-8.5, P = 0.03). HER-2/neu status was not a factor in predicting objective response to different anthracycline dose intensities. The same finding was observed with regards to HR and Ki67. CONCLUSIONS In our series, no significant dose-response relationship was found according to HER-2/neu status. | Evaluation of HER-2/neu amplification and other biological markers as predictors of response to neoadjuvant anthracycline-based chemotherapy in primary breast cancer: the role of anthracycline dose intensity. |
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0.021256839856505394, "28828": 0.4855078160762787, "28829": 0.4145384132862091, "28847": 0.8583967685699463, "28927": 0.23324857652187347, "29238": 0.055094651877880096} | 24863571 | The mammalian mitochondrial genome contains 37 genes, 13 of which encode polypeptide subunits in the enzyme complexes of the oxidative phosphorylation system. The other genes encode the rRNAs and tRNAs necessary for their translation. The mitochondrial translation machinery is located in the mitochondrial matrix, and is exclusively dedicated to the synthesis of these 13 enzyme subunits. Mitochondrial disease in humans is often associated with defects in mitochondrial translation. This can manifest as a global decrease in the rate of mitochondrial protein synthesis, a decrease in the synthesis of specific polypeptides, the synthesis of abnormal polypeptides, or in altered stability of specific translation products. All of these changes in the normal pattern of mitochondrial translation can be assessed by a straightforward technique that takes advantage of the insensitivity of the mitochondrial translation machinery to antibiotics that completely inhibit cytoplasmic translation. Thus, specific radioactive labeling of the mitochondrial translation products can be achieved in cultured cells, and the results can be visualized on gradient gels. The analysis of mitochondrial translation in cells cultured from patient biopsies is useful in the study of disease-causing mutations in both the mitochondrial and the nuclear genomes. | Radioactive labeling of mitochondrial translation products in cultured cells. |
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While cyclins A1 and B are most closely related to either A- or B-type cyclins of other species, cyclin B3 is less related to these cyclins. However, this cyclin is most similar to the recently identified chicken cyclin B3. Our identification of a Caenorhabditis homolog demonstrates that cyclin B3 has been conserved in evolution. Cyclin A1 is a member of an A-type multigene family; however the cyclin A1 cDNA only recognizes a single band on northern blots. A single-sized RNA is also observed for the cyclin B3 cDNA. In contrast, three different transcripts are observed for the cyclin B cDNA. Based on our analyses using RNAs from germline-defective mutants and from populations enriched for males, one cyclin B transcript is specific to the paternal germline. The two other cyclin B transcripts, as well as the cyclin A1 and cyclin B3 transcripts, are most abundant in the maternal germline and are only present at low levels in other tissues. Moreover, the 3' untranslated regions of each Caenorhabditis cyclin cDNA possess several copies of potential translational control elements shown in Xenopus and Drosophila maternal cyclin mRNAs to function during oogenesis and early embryogenesis. | Caenorhabditis elegans cyclin A- and B-type genes: a cyclin A multigene family, an ancestral cyclin B3 and differential germline expression. |
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"26456": 0.8109301924705505, "26497": 0.5795059204101562, "28297": 0.09761575609445572, "28667": 0.7258110046386719, "29234": 0.24325250089168549, "29264": 0.8039615154266357, "29299": 0.19862671196460724, "29443": 0.20501139760017395, "29486": 0.020300358533859253} | 24865781 | Forty-one recurrent tension headache sufferers were randomly assigned to either cognitive-behavioral therapy (administered in a primarily home-based treatment protocol) or to amitriptyline therapy (with dosage individualized at 25, 50, or 75 mg/day). Cognitive-behavioral therapy and amitriptyline each yielded clinically significant improvements in headache activity, both when improvement was assessed with patient daily recordings (56% and 27% reduction in headache index, respectively), and when improvement was assessed with neurologist ratings of clinical improvement (94% and 69% of patients rated at least moderately improved, respectively). In instances where differences in treatment effectiveness were observed (headache index, somatic complaints, perceptions of control of headache activity), cognitive-behavioral therapy yielded somewhat more positive outcomes than did amitriptyline. Neither treatment, however, eliminated headache problems. | A comparison of pharmacological (amitriptyline HCL) and nonpharmacological (cognitive-behavioral) therapies for chronic tension headaches. |
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0.15526613593101501, "26657": 0.012615402229130268, "26721": 0.8117979168891907, "26745": 0.045809537172317505, "26786": 0.2990913391113281, "27453": 0.08603433519601822, "27854": 0.11081436276435852, "28155": 0.10291612148284912, "28227": 0.5778634548187256, "28309": 0.004870930220931768, "28436": 0.5662899017333984, "28696": 1.276475191116333, "28794": 0.0019512200960889459, "29125": 0.03360854089260101, "29235": 0.14939609169960022, "29458": 0.9217445850372314, "29490": 0.10291612148284912} | 24872571 | The steady-state basal plasma glucose and insulin concentrations are determined by their interaction in a feedback loop. A computer-solved model has been used to predict the homeostatic concentrations which arise from varying degrees of β-cell deficiency and insulin resistance. Comparison of a patient's fasting values with the model's predictions allows a quantitative assessment of the contributions of insulin resistance and deficient β-cell function to the fasting hyperglycaemia (homeostasis model assessment, HOMA). The accuracy and precision of the estimate have been determined by comparison with independent measures of insulin resistance and β-cell function using hyperglycaemic and euglycaemic clamps and an intravenous glucose tolerance test. The estimate of insulin resistance obtained by homeostasis model assessment correlated with estimates obtained by use of the euglycaemic clamp (Rs = 0.88, p < 0.0001), the fasting insulin concentration (Rs = 0.81, p < 0.0001), and the hyperglycaemic clamp, (Rs = 0.69, p < 0.01). There was no correlation with any aspect of insulin-receptor binding. The estimate of deficient β-cell function obtained by homeostasis model assessment correlated with that derived using the hyperglycaemic clamp (Rs = 0.61, p < 0.01) and with the estimate from the intravenous glucose tolerance test (Rs = 0.64, p < 0.05). The low precision of the estimates from the model (coefficients of variation: 31% for insulin resistance and 32% for β-cell deficit) limits its use, but the correlation of the model's estimates with patient data accords with the hypothesis that basal glucose and insulin interactions are largely determined by a simple feed back loop. | Homeostasis model assessment: insulin resistance and β-cell function from fasting plasma glucose and insulin concentrations in man |
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0.5534584522247314, "29172": 0.3485364317893982, "29391": 0.25845035910606384} | 24873253 | Patients with metastatic bone disease are at risk for developing skeletal-related events that can negatively influence quality of life, contributing to loss of autonomy and functional capabilities. Bisphosphonates have become an important component in the treatment of patients with bone metastases as they delay the onset and reduce the risk of skeletal-related events and also palliate or control bone pain in multiple cancer types, thus preserving quality of life. Zoledronic acid has proven efficacy and safety in patients with bone lesions from breast cancer, prostate cancer, lung cancer, and other solid tumors, as well as in patients with multiple myeloma. Current data suggest that early treatment with zoledronic acid (before the onset of bone pain) may provide additional clinical benefits and also positive effects on survival in subsets of patients who have elevated levels of N-telopeptide of type I collagen (NTX), a biochemical marker of bone resorption. Studies have shown that in patients with breast cancer, prostate cancer, lung cancer, or other solid tumors, normalization of elevated levels of NTX was observed in the majority of patients who received zoledronic acid. Furthermore, normalization of NTX values correlated with extended survival. | Clinical benefits and considerations of bisphosphonate treatment in metastatic bone disease. |
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However, it remains unclear whether there are CD4(+) memory T cells committed to the Tfh cell lineage after antigen clearance. By using adoptive transfer of antigen-specific memory CD4(+) T cell subpopulations in the lymphocytic choriomeningitis virus infection model, we found that there are distinct memory CD4(+) T cell populations with commitment to either Tfh- or Th1-cell lineages. Our conclusions are based on gene expression profiles, epigenetic studies, and phenotypic and functional analyses. Our findings indicate that CD4(+) memory T cells "remember" their previous effector lineage after antigen clearance, being poised to reacquire their lineage-specific effector functions upon antigen reencounter. These findings have important implications for rational vaccine design, where improving the generation and engagement of memory Tfh cells could be used to enhance vaccine-induced protective immunity. | Distinct memory CD4+ T cells with commitment to T follicular helper- and T helper 1-cell lineages are generated after acute viral infection. |
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"28086": 0.07068414986133575, "28228": 0.1358480453491211, "28327": 0.7482418417930603, "28466": 0.014542185701429844, "28685": 0.10203468054533005, "28828": 0.6389714479446411, "28829": 0.053244512528181076, "29101": 0.23247487843036652, "29129": 0.6286086440086365, "29401": 0.3170322775840759, "29477": 0.018384648486971855, "29516": 0.06795065850019455} | 24881307 | Synapses are specialized cell-cell contacts that mediate communication between neurons. Most excitatory synapses in the brain are housed on dendritic spines, small actin-rich protrusions extending from dendrites. During development and in response to environmental stimuli, spines undergo marked changes in shape and number thought to underlie processes like learning and memory. Improper spine development, in contrast, likely impedes information processing in the brain, since spine abnormalities are associated with numerous brain disorders. Elucidating the mechanisms that regulate the formation and plasticity of spines and their resident synapses is therefore crucial to our understanding of cognition and disease. Rho-family GTPases, key regulators of the actin cytoskeleton, play essential roles in orchestrating the development and remodeling of spines and synapses. Precise spatio-temporal regulation of Rho GTPase activity is critical for their function, since aberrant Rho GTPase signaling can cause spine and synapse defects as well as cognitive impairments. Rho GTPases are activated by guanine nucleotide exchange factors (GEFs) and inhibited by GTPase-activating proteins (GAPs). We propose that Rho-family GEFs and GAPs provide the spatiotemporal regulation and signaling specificity necessary for proper Rho GTPase function based on the following features they possess: (i) existence of multiple GEFs and GAPs per Rho GTPase, (ii) developmentally regulated expression, (iii) discrete localization, (iv) ability to bind to and organize specific signaling networks, and (v) tightly regulated activity, perhaps involving GEF/GAP interactions. Recent studies describe several Rho-family GEFs and GAPs that uniquely contribute to spinogenesis and synaptogenesis. Here, we highlight several of these proteins and discuss how they occupy distinct biochemical niches critical for synaptic development. | Control of synapse development and plasticity by Rho GTPase regulatory proteins |
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In this report, we analyze spontaneous mutations accumulated over thousands of generations by wild-type Escherichia coli and a derivative defective in mismatch repair (MMR), the primary pathway for correcting replication errors. The major conclusions are (i) the mutation rate of a wild-type E. coli strain is ~1 × 10(-3) per genome per generation; (ii) mutations in the wild-type strain have the expected mutational bias for G:C > A:T mutations, but the bias changes to A:T > G:C mutations in the absence of MMR; (iii) during replication, A:T > G:C transitions preferentially occur with A templating the lagging strand and T templating the leading strand, whereas G:C > A:T transitions preferentially occur with C templating the lagging strand and G templating the leading strand; (iv) there is a strong bias for transition mutations to occur at 5'ApC3'/3'TpG5' sites (where bases 5'A and 3'T are mutated) and, to a lesser extent, at 5'GpC3'/3'CpG5' sites (where bases 5'G and 3'C are mutated); (v) although the rate of small (≤4 nt) insertions and deletions is high at repeat sequences, these events occur at only 1/10th the genomic rate of base-pair substitutions. MMR activity is genetically regulated, and bacteria isolated from nature often lack MMR capacity, suggesting that modulation of MMR can be adaptive. Thus, comparing results from the wild-type and MMR-defective strains may lead to a deeper understanding of factors that determine mutation rates and spectra, how these factors may differ among organisms, and how they may be shaped by environmental conditions. | Rate and molecular spectrum of spontaneous mutations in the bacterium Escherichia coli as determined by whole-genome sequencing. |
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0.18978065252304077, "29237": 0.02316705882549286} | 24906548 | The epsilon4 allele of the apolipoprotein E (APOE) gene has been linked to negative outcomes among adults with traumatic brain injury (TBI) across the spectrum of severity, with preliminary evidence suggesting a similar pattern among children. This study investigated the relationship of the APOE epsilon4 allele to outcomes in children with mild TBI. Participants in this prospective, longitudinal study included 99 children with mild TBI between the ages of 8 and 15 recruited from consecutive admissions to Emergency Departments at two large children's hospitals. Outcomes were assessed acutely in the Emergency Department and at follow-ups at 2 weeks, 3 months, and 12 months post-injury. Among the 99 participants, 28 had at least one epsilon4 allele. Children with and without an epsilon4 allele did not differ demographically. Children with an epsilon4 allele were significantly more likely than those without an epsilon4 allele to have a Glasgow Coma Scale score of less than 15, but the groups did not differ on any other measures of injury severity. Those with an epsilon4 allele exhibited better performance than children without an epsilon4 allele on a test of constructional skill, but the groups did not differ on any other neuropsychological tests. Children with and without an epsilon4 allele also did not differ on measures of post-concussive symptoms. Overall, the findings suggest that the APOE epsilon4 allele is not consistently related to the outcomes of mild TBI in children. | Apolipoprotein E4 as a predictor of outcomes in pediatric mild traumatic brain injury. |
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0.06795065850019455, "27531": 0.04394211992621422, "27673": 0.3870677351951599, "27921": 0.16524957120418549, "28207": 0.03831886500120163, "28393": 0.0009760859538801014, "28582": 0.151916041970253, "28926": 0.1477125883102417, "28929": 0.09850110858678818, "29278": 0.12814582884311676} | 24916604 | BACKGROUND The use of bisphosphonates for the prevention of skeletal related events in women with bone metastases from breast cancer is well established. We undertook an evaluation of bisphosphonate use in clinical practice in three Canadian cancer centres. In addition we assessed whether or not physicians at these centres are following their local treatment guidelines and funding policies. METHODS Charts and electronic files of patients who had received either clodronate or pamidronate at any time between January 2000 and December 2001 at three Canadian cancer centres were retrospectively reviewed. RESULTS There has been a marked improvement in the time between the diagnosis of bone metastases and the commencement of bisphosphonates from a median of 155 days in 1998 to 24 days in 2001. However, despite a local funding policy requiring that oral clodronate be the first bisphosphonate used, this was the case in only 67% of patients. In addition, despite one centre's guidelines recommending that bisphosphonates be stopped once the patient was progressing, 90% of their patients remained on bisphosphonates until they died. CONCLUSIONS A considerable amount of effort is spent on the creation of "evidence based" treatment guidelines. Funding agencies develop policies based on these treatment guidelines, but often funding is more restrictive than the treatment guideline would suggest. It is clear from this review that physicians still appear to manage a substantial proportion of patients outside of funding policies, but within evidence based recommendations. Therefore, a need exists for either the creation of guidelines and policies that physicians will follow or the implementation of methods to ensure that restrictive policies are actually followed. | Do physicians follow systemic treatment and funding policy guidelines? |
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0.029824240133166313, "27531": 0.09495500475168228, "27642": 0.04113444685935974, "27697": 0.10291612148284912, "27781": 0.32058215141296387, "27788": 0.35745587944984436, "27790": 0.08871890604496002, "27854": 0.2247048318386078, "28173": 0.7172679901123047, "28286": 0.5844172835350037, "28287": 0.2478361576795578, "28295": 0.08513788133859634, "28329": 0.15442965924739838, "28696": 0.09938567131757736, "28873": 0.1384023278951645, "29166": 0.9680526852607727, "29191": 0.12038381397724152, "29295": 0.12986256182193756, "29458": 0.03831886500120163, "29490": 1.020087480545044} | 24917562 | PURPOSE To determine whether an increased resting energy expenditure (REE) and weight loss in lung cancer patients are related to a systemic inflammatory response. MATERIALS AND METHODS REE was measured by indirect calorimetry using a ventilated hood system. Soluble tumor necrosis factor receptor 55 (sTNF-R55) and sTNF-R75, soluble intercellular adhesion molecule (sICAM)-1, soluble E (sE)-selectin, lipopolysaccharide (LPS)-binding protein (LBP), interleukin (IL)-6, and TNF-alpha were measured using sandwich enzyme-linked immunosorbent assay (ELISA), and C-reactive protein (CRP) was measured by turbidimetry. A cross-sectional study was performed to compare inflammatory mediators between hypermetabolic (REE/Harris Benedict [HB] equation > or = 110%) versus normometabolic (REE/HB < 110%) patients and between patients who lost weight (more than 10% loss of preillness weight) versus those whose weight remained stable. RESULTS Eighty-seven patients with primary non-small-cell lung cancer were consecutively entered onto the study. Mean REE expressed as a percentage of the HB reference values was 118% +/- 12%; 67 patients were considered hypermetabolic. Twenty-six patients had a substantial loss of more than 10% of their preillness weight. Hypermetabolic patients were found to have significantly increased levels of sTNF-R55, sE-selectin, LBP, and CRP compared with normometabolic patients. Weight loss was related with increased levels of the sTNF-Rs, sICAM-1, IL-6, LBP, and CRP. CONCLUSION Hypermetabolism and weight loss are related to the presence of a systemic inflammatory response as reflected by enhanced levels of inflammatory mediators and acute phase proteins in patients with primary non-small-cell lung cancer. | Increased resting energy expenditure and weight loss are related to a systemic inflammatory response in lung cancer patients. |
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0.011650617234408855, "27891": 0.015504186972975731, "28093": 0.21687394380569458, "28309": 0.23479416966438293, "28321": 0.09672962874174118, "28353": 0.043007105588912964, "28428": 0.8374842405319214, "28436": 0.036437395960092545, "28591": 0.06703783571720123, "28689": 0.036437395960092545, "28732": 0.015504186972975731, "29160": 1.0285027027130127, "29166": 0.0058422754518687725, "29458": 0.21765978634357452, "29525": 0.7144040465354919} | 24918110 | OBJECTIVE To demonstrate the relation of exercise capacity and BMI to mortality in a population of male veterans with type 2 diabetes. RESEARCH DESIGN AND METHODS After excluding two underweight patients (BMI <18.5 kg/m2), the study population comprised 831 consecutive patients with type 2 diabetes (mean age 61 +/- 9 years) referred for exercise testing for clinical reasons between 1995 and 2006. Exercise capacity was determined from a maximal exercise test and measured in metabolic equivalents (METs). Patients were classified both according to BMI category (18.5-24.9, 25.0-29.9, and > or =30 kg/m2) and by exercise capacity (<5.0 or > or =5.0 maximal METs). The association among exercise capacity, BMI, other clinical variables, and all-cause mortality was assessed by Cox proportional hazards. Study participants were followed for mortality up to 30 June 2006. RESULTS During a mean follow-up of 4.8 +/- 3.0 years, 112 patients died, for an average annual mortality rate of 2.2%. Each 1-MET increase in exercise capacity conferred a 10% survival benefit (hazard ratio 0.90 [95% CI 0.82-0.98]; P = 0.01), but BMI was not significantly associated with mortality. After adjustment for age, ethnicity, examination year, BMI, presence of cardiovascular disease (CVD), and CVD risk factors, diabetic patients achieving <5 maximal METs were 70% more likely to die (1.70 [1.13-2.54]) than those achieving > or =5 maximal METs. CONCLUSIONS There was a strong inverse association between exercise capacity and mortality in this cohort of men with documented diabetes, and this relationship was independent of BMI. | Exercise capacity and body mass as predictors of mortality among male veterans with type 2 diabetes. |
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0.07250232994556427, "25032": 0.46853771805763245, "25172": 1.12938392162323, "25311": 0.2394166737794876, "25456": 0.045809537172317505, "25643": 0.2409527748823166, "25644": 0.3877306580543518, "25986": 0.11604541540145874, "26014": 0.3297532796859741, "26452": 0.2830325961112976, "26651": 0.06246116757392883, "26657": 0.176772341132164, "26773": 0.3777405619621277, "27427": 0.09672962874174118, "28227": 0.6461620330810547, "28466": 0.19381128251552582, "28696": 0.3304552733898163, "29125": 0.083342544734478, "29516": 0.1619328260421753, "29750": 0.05046287178993225} | 24921368 | Impaired awareness of hypoglycaemia (IAH) is an acquired complication of insulin therapy, which affects people with type 1 and insulin-treated type 2 diabetes mellitus, whereby the ability to perceive the onset of hypoglycaemia becomes diminished or absent. Deficiencies of the counter-regulatory hormonal responses to hypoglycaemia usually co-exist. The development of IAH and counter-regulatory failure greatly increases the risk of severe hypoglycaemia. Scoring systems have been developed that can be used in the clinical setting and assist with identification of this group of individuals at risk of severe hypoglycaemia. The mainstay of treatment of IAH is the scrupulous avoidance of hypoglycaemia. | Impaired awareness of hypoglycaemia: a review. |
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0.630689799785614, "29361": 0.04860413447022438} | 24922825 | Traditionally, vaccine development involves tradeoffs between immunogenicity and safety. Live-attenuated vaccines typically offer rapid and durable immunity but have reduced safety when compared to inactivated vaccines. In contrast, the inability of inactivated vaccines to replicate enhances safety at the expense of immunogenicity, often necessitating multiple doses and boosters. To overcome these tradeoffs, we developed the insect-specific alphavirus, Eilat virus (EILV), as a vaccine platform. To address the chikungunya fever (CHIKF) pandemic, we used an EILV cDNA clone to design a chimeric virus containing the chikungunya virus (CHIKV) structural proteins. The recombinant EILV/CHIKV was structurally identical at 10 Å to wild-type CHIKV, as determined by single-particle cryo-electron microscopy, and it mimicked the early stages of CHIKV replication in vertebrate cells from attachment and entry to viral RNA delivery. Yet the recombinant virus remained completely defective for productive replication, providing a high degree of safety. A single dose of EILV/CHIKV produced in mosquito cells elicited rapid (within 4 d) and long-lasting (>290 d) neutralizing antibodies that provided complete protection in two different mouse models. In nonhuman primates, EILV/CHIKV elicited rapid and robust immunity that protected against viremia and telemetrically monitored fever. Our EILV platform represents the first structurally native application of an insect-specific virus in preclinical vaccine development and highlights the potential application of such viruses in vaccinology. | A chikungunya fever vaccine utilizing an insect-specific virus platform |
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0.16442140936851501, "26417": 0.18978065252304077, "26443": 0.29036402702331543, "26651": 0.9256220459938049, "26780": 0.0842406153678894, "27099": 0.5261374711990356, "27142": 0.27044451236724854, "27226": 0.04860413447022438, "27295": 0.32199856638908386, "27446": 0.6548244953155518, "27598": 0.4425300657749176, "28086": 0.016465263441205025, "28228": 0.03360854089260101, "28406": 0.030771657824516296, "28479": 0.9271688461303711, "28910": 0.007782140281051397, "29516": 0.006812678650021553, "29598": 0.7389566898345947} | 24923605 | Oxygen and its limitation are emerging as a crucial factor in plant fitness, growth and development. Recent studies revealed the mechanisms by which oxygen is perceived by plant cells. This sensory system partly relies on an oxygen-mediated branch of the N-end rule pathway for protein degradation acting on a specific clade of ethylene responsive transcription factors (ERF-VII). A complementary regulative step is provided by aerobic sequestration of an ERF-VII protein at the plasma membrane and its timely release when hypoxia occurs. Complete absence of oxygen triggers the transient accumulation of reactive hydrogen peroxide and induces an additional set of reactive oxygen species-related genes involved in both signaling and attenuation of oxidative stress. Moreover, temporary hypoxic environments that are built up as consequence of dense cell packing have been demonstrated to trigger cell-fate determination in maize anthers. Similarly, limited oxygen delivery in bulky fruit or tuber tissues growing in aerobic conditions were shown to stimulate anaerobic-like responses. These advances in low-oxygen signaling and its effect on cell development highlight the importance of taking hypoxia into account in agronomical practices as well as in breeding programs. | Molecular elements of low-oxygen signaling in plants. |
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0.012615402229130268, "27177": 0.25088030099868774, "27233": 0.7370892763137817, "27631": 0.5116065740585327, "27673": 0.28890204429626465, "27697": 0.24018502235412598, "27790": 0.4374985992908478, "27887": 0.16607704758644104, "28361": 0.014542185701429844, "28406": 0.9209672808647156, "28591": 0.1477125883102417, "28613": 0.09850110858678818, "28695": 0.1229778528213501, "28715": 0.0029254043474793434, "28716": 0.3601844012737274, "28873": 0.23402166366577148, "29090": 0.3170322775840759, "29172": 0.026025565341114998, "29393": 0.16110190749168396, "29458": 0.36426326632499695, "29484": 0.04487626627087593, "29587": 0.0317181795835495} | 24928817 | The initiation and progression of adult-onset periodontitis has been associated with infection of the gingival sulcus by Porphyromonas gingivalis. This organism utilizes a multitude of virulence factors to evade host defenses as it establishes itself as one of the predominant pathogens in periodontal pockets. A feature common to many other oral pathogens is the production of ammonia due to its protective effect during acidic cleansing cycles in the mouth. Additionally, ammonia production by P. gingivalis has been proposed as a virulence factor due to its negative effects on neutrophil function. In this study, we describe the first purification of a peptidylarginine deiminase (PAD) from a prokaryote. PAD exhibits biochemical characteristics and properties that suggest that it may be a virulence agent. PAD deiminates the guanidino group of carboxyl-terminal arginine residues on a variety of peptides, including the vasoregulatory peptide-hormone bradykinin, to yield ammonia and a citrulline residue. The soluble protein has an apparent mass of 46 kDa, while the DNA sequence predicts a full-length protein of 61.7 kDa. PAD is optimally active at 55 degrees C, stable at low pH, and shows the greatest activity above pH 9.0. Interestingly, in the presence of stabilizing factors, PAD is resistant to limited proteolysis and retains significant activity after short-term boiling. We propose that PAD, acting in concert with arginine-specific proteinases from P. gingivalis, promotes the growth of the pathogen in the periodontal pocket, initially by enhancing its survivability and then by assisting the organism in its circumvention of host humoral defenses. | Purification, characterization, and sequence analysis of a potential virulence factor from Porphyromonas gingivalis, peptidylarginine deiminase. |
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"27373": 0.27934664487838745, "27532": 0.21530038118362427, "27811": 0.11256109178066254, "28117": 0.19220098853111267, "28297": 0.8845420479774475, "28767": 0.09761575609445572, "28816": 0.0797421783208847, "29264": 0.055094651877880096, "29292": 0.10026945173740387, "29316": 0.21135559678077698, "29349": 0.23787821829319, "29458": 0.4318077862262726, "29486": 0.5968599319458008, "29494": 0.5685047507286072, "29516": 0.13414156436920166} | 24942840 | OBJECTIVES To determine the frequency of neurobehavioral signs and symptoms reported in every published case of traumatic encephalopathy with a view toward the development of clinical diagnostic criteria with predictive validity. INTRODUCTION Cases of persistent or progressive neurological or neurobehavioral change following exposure to one or more head injuries have been reported since 1928. This condition is often referred to as traumatic encephalopathy (TE). To date, however, no diagnostic criteria have been advanced or accepted for the clinical diagnosis of TE. Provisional research diagnostic criteria are required not only for meaningful diagnosis but also to facilitate research to determine the epidemiology, etiology, course, prognosis, imaging and biomarkers, neuropathological features and potentially effective treatments of TE. METHODS All 436 published cases of TE in all languages were reviewed. All symptoms and signs reported in these cases were classified and enumerated. RESULTS Ninety-seven cases met inclusion criteria based on sufficient documentation of the history and neurobehavioral examination. Provisional research diagnostic criteria for clinically probable and clinically possible TE were developed based on the most frequently reported clinical features. CONCLUSION The provisional diagnostic criteria for TE presented here are the first published criteria for this condition based upon a systematic analysis of its clinical characteristics. This is the first a step toward scientifically derived consensus criteria, which are essential to accelerate progress in the investigation of this important condition. | Traumatic encephalopathy: review and provisional research diagnostic criteria. |
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1.1211429834365845, "29172": 0.14179791510105133, "29308": 0.03360854089260101, "29391": 0.3248254358768463, "29486": 0.34023189544677734, "29494": 0.3956514894962311} | 24943534 | In the United States, an estimated 200,000 persons are infected with both hepatitis C virus (HCV) and human immunodeficiency virus (HIV). As the lives of HIV-infected persons have been prolonged by use of highly active antiretroviral therapy, liver disease has emerged as an important, and in some settings, the leading cause of morbidity and mortality. Human immunodeficiency virus infection appears to adversely affect all stages of hepatitis C infection, leading to increased viral persistence and accelerated progression of HCV-related liver disease. In turn, hepatitis C may affect the management of HIV infection, increasing the incidence of liver toxicity caused by antiretroviral medications. The medical management of hepatitis C in HIV-infected persons remains controversial, in part because of the complexity of both infections and potential drug interactions, but chiefly because there is so little published information. Nonetheless, the burden of liver disease is too high to delay management of HIV/HCV-coinfected persons while awaiting better data. Instead, the management of hepatitis C today must be based on data generated on persons without HIV and an understanding of both infections. Properly designed studies of therapy in HIV/HCV-coinfected persons are needed to help guide management of these patients in the future. | Hepatitis C and human immunodeficiency virus infection. |
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24974080 | New blood vessel formation (angiogenesis) is a fundamental event in the process of tumor growth and metastatic dissemination. Hence, the molecular basis of tumor angiogenesis has been of keen interest in the field of cancer research. The vascular endothelial growth factor (VEGF) pathway is well established as one of the key regulators of this process. The VEGF/VEGF-receptor axis is composed of multiple ligands and receptors with overlapping and distinct ligand-receptor binding specificities, cell-type expression, and function. Activation of the VEGF-receptor pathway triggers a network of signaling processes that promote endothelial cell growth, migration, and survival from pre-existing vasculature. In addition, VEGF mediates vessel permeability, and has been associated with malignant effusions. More recently, an important role for VEGF has emerged in mobilization of endothelial progenitor cells from the bone marrow to distant sites of neovascularization. The well-established role of VEGF in promoting tumor angiogenesis and the pathogenesis of human cancers has led to the rational design and development of agents that selectively target this pathway. Studies with various anti-VEGF/VEGF-receptor therapies have shown that these agents can potently inhibit angiogenesis and tumor growth in preclinical models. Recently, an anti-VEGF antibody (bevacizumab), when used in combination with chemotherapy, was shown to significantly improve survival and response rates in patients with metastatic colorectal cancer and thus, validate VEGF pathway inhibitors as an important new treatment modality in cancer therapy. | Role of the vascular endothelial growth factor pathway in tumor growth and angiogenesis. |
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RMA performs background correction, normalization, and summarization in a modular way. The last 2 steps require multiple arrays to be analyzed simultaneously. The ability to borrow information across samples provides RMA various advantages. For example, the summarization step fits a parametric model that accounts for probe effects, assumed to be fixed across arrays, and improves outlier detection. Residuals, obtained from the fitted model, permit the creation of useful quality metrics. However, the dependence on multiple arrays has 2 drawbacks: (1) RMA cannot be used in clinical settings where samples must be processed individually or in small batches and (2) data sets preprocessed separately are not comparable. We propose a preprocessing algorithm, frozen RMA (fRMA), which allows one to analyze microarrays individually or in small batches and then combine the data for analysis. This is accomplished by utilizing information from the large publicly available microarray databases. In particular, estimates of probe-specific effects and variances are precomputed and frozen. Then, with new data sets, these are used in concert with information from the new arrays to normalize and summarize the data. We find that fRMA is comparable to RMA when the data are analyzed as a single batch and outperforms RMA when analyzing multiple batches. The methods described here are implemented in the R package fRMA and are currently available for download from the software section of http://rafalab.jhsph.edu. | Frozen robust multiarray analysis (fRMA). |
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0.07793712615966797, "26927": 0.2317005842924118, "27094": 0.5618454217910767, "27144": 0.255429208278656, "27453": 0.4926934838294983, "27781": 0.3318578004837036, "27854": 0.13157635927200317, "28105": 0.26146242022514343, "28177": 0.036437395960092545, "28309": 0.07884006202220917, "28370": 0.2026219218969345, "28389": 0.13499516248703003, "28616": 0.5751199722290039, "28873": 0.48670899868011475, "29490": 0.19862671196460724} | 24980622 | PURPOSE To investigate hypoxia measured by pimonidazole binding, glucose transporter 1 (GLUT1) and carbonic anhydrase IX (CA-IX) expression, proliferation, and vascularity in liver metastases of colorectal cancer and to compare GLUT1 and CA-IX expression in corresponding primary tumors. METHODS AND MATERIALS Twenty-five patients with liver metastases of colorectal cancer, planned for metastasectomy, were included. The hypoxia marker pimonidazole and proliferation marker iododeoxyuridine were administered before surgery. After immunofluorescent staining of the frozen metastases, pimonidazole binding, vascularity, and proliferation were analyzed quantitatively. Thirteen paraffin-embedded primary tumors were stained immunohistochemically for GLUT1 and CA-IX expression, which was analyzed semiquantitatively in primary tumors and corresponding liver metastases. RESULTS In liver metastases, pimonidazole binding showed a pattern consistent with diffusion-limited hypoxia. The mean pimonidazole-positive fraction was 0.146; the mean distance from vessels to pimonidazole-positive areas was 80 microm. When expressed, often co-localization was observed between pimonidazole binding and GLUT1 or CA-IX expression, but microregional areas of mismatch were also observed. No correlation between the level of pimonidazole binding and GLUT1 or CA-IX expression was observed. In some patients, a large fraction (up to 30%) of proliferating cells was present in pimonidazole-stained areas. Expression of CA-IX in primary tumors and metastases showed a significant correlation, which was absent for GLUT1 expression. CONCLUSIONS Compared with other tumor types, liver metastases of colorectal cancer contain large amounts of hypoxic cells. The lack of correlation with pimonidazole binding brings into question the value of GLUT1 and CA-IX as endogenous markers of hypoxia. | Hypoxia in relation to vasculature and proliferation in liver metastases in patients with colorectal cancer. |
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"29060": 0.1602703034877777, "29215": 0.1873544454574585, "29251": 0.3374483287334442, "29277": 0.22392450273036957, "29295": 0.10818854719400406, "29353": 0.06337817758321762, "29458": 0.01934296265244484, "29486": 0.28155985474586487} | 24988745 | This study aimed to compare the symptoms, unmet needs, and QoL reported by women at 6 months to <2 years and 2 to 5 years following surgery and adjuvant treatment for breast cancer. It also evaluated the relationships among symptoms, unmet needs, and QoL using structural equation modeling. In this study, 113 and 137 survivors following breast cancer treatment 6 months to <2 years and 2 to 5 years, respectively, completed the Memorial Symptom Assessment Scale, the Supportive Care Needs Survey-34, and the Medical Outcomes Study 12-item Short Form Health Survey version 2.0 during their medical follow-up. The mean numbers of symptoms and unmet needs were 5.43 and 3.0, respectively, for survivors at <2 years, and 5.24 and 2.42, respectively, for survivors at 2 to 5 years following treatment. The most common reported symptoms were related primarily to physical domains. No significant differences were found between the two survivor groups on the MSAS scores. Survivors at <2 years reported significantly higher scores in Psychological and Health Care System/Information needs (p < 0.01), and lower composite scores in physical and mental QoL (p < 0.05) than those at 2 to 5 years post-treatment. Significant direct and indirect effects were found of symptom burden through unmet needs on survivors’ physical and mental QoL after adjustment for survival time, and the models showed a good fit. Results suggest that breast cancer survivors continue to endure many symptoms independent of the survivorship period. The unmet needs mediate the relationship between symptom burden and survivors’ QoL. | Unmet needs mediate the relationship between symptoms and quality of life in breast cancer survivors |
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0.3588210940361023, "28873": 0.2184450328350067, "28915": 0.2145126610994339, "29090": 0.0029254043474793434, "29290": 0.33953672647476196, "29486": 0.3519764244556427, "29543": 0.1064341589808464} | 24989194 | The presence of extracellular deposits of beta-amyloid protein in the brain is a hallmark of Alzheimer's disease (AD). In an effort to determine the effect of amyloid in an animal model, the authors injected amyloid cores isolated from AD brains into the cortex and hippocampus of rats. Lipofuscin, a major contaminant of the plaque core preparation, was injected on the contralateral side and used as a control to induce an analogous phagocytic cell response. Rats were sacrificed 2 days, 7 days, and 1 month after injection and amyloid located by four histochemical techniques. Amyloid and lipofuscin move from the site of injection into otherwise undamaged neuropil, persist for at least 1 month and are both associated with increases in glial fibrillary acidic protein and microglia (OX-42) staining. By 1 week, many of the amyloid cores are ingested by phagocytes. Some of the beta-amyloid-containing phagocytes migrate to the vessels and to the ventricles, and by 1 month, a significant amount of the amyloid is directly associated with the vessels. This suggests that phagocytic cells can internalize exogenous amyloid and attempt to clear it from the central nervous system (CNS). Therefore, the observed distribution of amyloid is not necessarily the initial site of deposition. | Phagocytosis and deposition of vascular beta-amyloid in rat brains injected with Alzheimer beta-amyloid. |
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"26244": 0.04767346754670143, "26402": 0.18329764902591705, "26773": 0.018384648486971855, "26874": 0.0842406153678894, "27065": 0.013579257763922215, "27642": 0.0354953333735466, "27777": 0.03360854089260101, "27854": 0.31132611632347107, "28086": 0.04674193635582924, "29278": 0.1677299439907074, "29290": 0.08782484382390976, "29292": 0.02316705882549286, "29489": 0.28082266449928284} | 24995939 | Recent studies have shown that the protein CTCF, which plays an important role in insulation and in large-scale organization of chromatin within the eukaryotic nucleus, depends for both activities on recruitment of the cohesin complex. We show here that the interaction of CTCF with the cohesin complex involves direct contacts between the cohesin subunit SA2 and specific regions of the C-terminal tail of CTCF. All other cohesin components are recruited through their interaction with SA2. Expression in vivo of CTCF mutants lacking the C-terminal domain, or with mutations at sites within it required for SA2 binding, disrupts the normal expression profile of the imprinted genes IGF2-H19 and also results in a loss of insulation activity. Taken together, our results demonstrate that specific sites on the C terminus of CTCF are essential for cohesin binding and insulator function. The only direct interaction between CTCF and cohesin involves contact with SA2, which is external to the cohesin ring. This suggests that in recruiting cohesin to CTCF, SA2 could bind first and the ring could assemble subsequently. | Specific sites in the C terminus of CTCF interact with the SA2 subunit of the cohesin complex and are required for cohesin-dependent insulation activity. |
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Both histological and immunological comparisons were made between IL-6-deficient (IL-6 -/-) mice and wild-type (IL-6 +/+) littermates after the induction of AIA. Although all IL-6 +/+ mice developed severe arthritis, only mild arthritis was observed in IL-6 -/- mice. Safranin O staining demonstrated that articular cartilage was well preserved in IL-6 -/- mice, whereas it was destroyed completely in IL-6 +/+ mice. In addition, comparable mRNA expression for both IL-1beta and tumor necrosis factor alpha, but not for IL-6, was detected in the inflamed joints of IL-6 -/- mice, suggesting that IL-6 may play a more crucial role in cartilage destruction than either IL-1beta or tumor necrosis factor alpha. In immunological comparisons, both antigen-specific in vitro proliferative response in lymph node cells and in vivo antibody production were elicited in IL-6 -/- mice, but they were reduced to less than half of that found in IL-6 +/+ mice. Lymph node cells of IL-6 -/- mice produced many more Th2 cytokines than did IL-6 +/+ mice with either antigen-specific or nonspecific stimulation in in vitro culture. Taken together, these results indicate that IL-6 may play a key role in the development of AIA at the inductive as well as the effector phase, and the blockade of IL-6 is possibly beneficial in the treatment of rheumatoid arthritis. | Interleukin 6 plays a key role in the development of antigen-induced arthritis. |
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The link between renal function and arterial stiffness was assessed in 305 patients with never-treated essential hypertension (men: 58%; age: 48+/-11 years, blood pressure: 151/95+/-20/11 mm Hg), free from overt cardiovascular disease and with serum creatinine values <1.4 mg/dL (men) and <1.2 mg/dL (women), who underwent noninvasive aortic and upper-limb pulse wave velocity (PWV) determination. Aortic PWV was strongly related to age (r=0.55; P<0.001), whereas upper-limb PWV had a weaker nonlinear relation with age (beta=1.392; P<0.001 for age; beta=-1.312; P<0.001 for age squared) and a weak relation with aortic PWV (r=0.22; P<0.001). Glomerular filtration rate (GFR), estimated according to the Mayo clinic equation for healthy subjects, was inversely correlated with large-artery stiffness, as assessed by aortic PWV (r=-0.34; P<0.001), and with peripheral artery stiffness, as assessed by upper-limb PWV (r=-0.25; P<0.001). In a multivariate linear regression, aortic PWV was independently predicted by age (beta=0.48; P<0.001), mean arterial pressure (beta=0.14; P=0.013), and GFR (beta=-0.13, P=0.029). Upper-limb PWV was predicted by GFR (beta=-0.24; P<0.001) and mean arterial pressure (beta=0.20; P<0.001). We conclude that, in hypertensive patients with normal renal function, an inverse relationship exists between GFR and stiffness of both central elastic and peripheral muscular arteries. These relations are in part independent from the effect of several confounders, including age, sex, and blood pressure values. | Relation between renal function within the normal range and central and peripheral arterial stiffness in hypertension. |
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"26534": 0.21214580535888672, "26773": 0.46117570996284485, "26775": 0.018384648486971855, "26874": 0.014542185701429844, "26942": 0.7546905279159546, "27152": 0.011650617234408855, "27321": 0.7333439588546753, "27854": 0.5220900774002075, "28406": 0.4267219603061676, "28788": 0.3519764244556427, "28848": 0.40285754203796387, "28873": 0.16690383851528168, "29021": 0.41065993905067444, "29060": 0.0913962796330452, "29490": 0.007782140281051397} | 25001628 | To identify previously unknown platelet receptors we compared the transcriptomes of in vitro differentiated megakaryocytes (MKs) and erythroblasts (EBs). RNA was obtained from purified, biologically paired MK and EB cultures and compared using cDNA microarrays. Bioinformatical analysis of MK-up-regulated genes identified 151 transcripts encoding transmembrane domain-containing proteins. Although many of these were known platelet genes, a number of previously unidentified or poorly characterized transcripts were also detected. Many of these transcripts, including G6b, G6f, LRRC32, LAT2, and the G protein-coupled receptor SUCNR1, encode proteins with structural features or functions that suggest they may be involved in the modulation of platelet function. Immunoblotting on platelets confirmed the presence of the encoded proteins, and flow cytometric analysis confirmed the expression of G6b, G6f, and LRRC32 on the surface of platelets. Through comparative analysis of expression in platelets and other blood cells we demonstrated that G6b, G6f, and LRRC32 are restricted to the platelet lineage, whereas LAT2 and SUCNR1 were also detected in other blood cells. The identification of the succinate receptor SUCNR1 in platelets is of particular interest, because physiologically relevant concentrations of succinate were shown to potentiate the effect of low doses of a variety of platelet agonists. | Comparative gene expression profiling of in vitro differentiated megakaryocytes and erythroblasts identifies novel activatory and inhibitory platelet membrane proteins. |
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"29137": 0.997294545173645, "29290": 0.13755162060260773, "29536": 0.09317722171545029, "29577": 0.13670019805431366} | 25007443 | In the hypothalamic arcuate nucleus (ARC), pro-opiomelanocortin (POMC) neurons inhibit feeding and neuropeptide-Y (NPY) neurons stimulate feeding. We tested whether neurons in the ventromedial hypothalamic nucleus (VMH), a known satiety center, activate anorexigenic neuronal pathways in the ARC by projecting either excitatory synaptic inputs to POMC neurons and/or inhibitory inputs to NPY neurons. Using laser scanning photostimulation in brain slices from transgenic mice, we found that POMC and NPY neurons, which are interspersed in the ARC, are nevertheless regulated by anatomically distinct synaptic inputs. POMC neurons received strong excitatory input from the medial VMH (mVMH), whereas NPY neurons did not and, instead, received weak inhibitory input only from within the ARC. The strength of the excitatory input from the mVMH to POMC neurons was diminished by fasting. These data identify a new molecularly defined circuit that is dynamically regulated by nutritional state in a manner consistent with the known role of the VMH as a satiety center. | Topographic mapping of VMH → arcuate nucleus microcircuits and their reorganization by fasting |
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human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT), I132M, which confers high-level resistance to the nonnucleoside RT inhibitors (NNRTIs) nevirapine and delavirdine. In this study, we have further characterized the role of this mutation in viral replication capacity and in resistance to other RT inhibitors. Surprisingly, our data show that I132M confers marked hypersusceptibility to the nucleoside analogs lamivudine (3TC) and tenofovir at both the virus and enzyme levels. Subunit-selective mutagenesis studies revealed that the mutation in the p51 subunit of RT was responsible for the increased sensitivity to the drugs, and transient kinetic analyses showed that this hypersusceptibility was due to I132M decreasing the enzyme's affinity for the natural dCTP substrate but increasing its affinity for 3TC-triphosphate. Furthermore, the replication capacity of HIV-1 containing I132M is severely impaired. This decrease in viral replication capacity could be partially or completely compensated for by the A62V or L214I mutation, respectively. Taken together, these results help to explain the infrequent selection of I132M in patients for whom NNRTI regimens are failing and furthermore demonstrate that a single mutation outside of the polymerase active site and inside of the p51 subunit of RT can significantly influence nucleotide selectivity. | The human immunodeficiency virus type 1 nonnucleoside reverse transcriptase inhibitor resistance mutation I132M confers hypersensitivity to nucleoside analogs. |
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0.8957691192626953, "24278": 1.1586239337921143, "24324": 0.35403475165367126, "24374": 0.306306391954422, "24587": 0.04767346754670143, "24848": 0.9724938273429871, "24905": 0.0058422754518687725, "25117": 0.013579257763922215, "25172": 0.5590575933456421, "25202": 0.36900100111961365, "25456": 0.4487839937210083, "25708": 0.17020416259765625, "25714": 0.9710156321525574, "26337": 0.6522845029830933, "26356": 1.0855059623718262, "26402": 0.9515975713729858, "26512": 0.8500841856002808, "26534": 0.21293537318706512, "26565": 0.38308101892471313, "26773": 0.8550800085067749, "26775": 0.24171993136405945, "27226": 0.41195443272590637, "27651": 0.04767346754670143, "27854": 0.0797421783208847, "28613": 0.5069117546081543, "28691": 0.06612417846918106, "28697": 0.4624064862728119, "28835": 0.05694137513637543, "28848": 0.17020416259765625, "29278": 0.22392450273036957, "29290": 0.07341018319129944} | 25022826 | AFF1 and AFF4 belong to the AFF (AF4/FMR2) family of proteins, which function as scaffolding proteins linking two different transcription elongation factors, positive elongation factor b (P-TEFb) and ELL1/2, in super elongation complexes (SECs). Both AFF1 and AFF4 regulate gene transcription through elongation and chromatin remodeling. However, their function in the osteogenic differentiation of mesenchymal stem cells (MSCs) is unknown. In this study, we show that small interfering RNA (siRNA)-mediated depletion of AFF1 in human MSCs leads to increased alkaline phosphatase (ALP) activity, enhanced mineralization and upregulated expression of osteogenic-related genes. On the contrary, depletion of AFF4 significantly inhibits the osteogenic potential of MSCs. In addition, we confirm that overexpression of AFF1 and AFF4 differentially affects osteogenic differentiation in vitro and MSC-mediated bone formation in vivo. Mechanistically, we find that AFF1 regulates the expression of DKK1 via binding to its promoter region. Depletion of DKK1 in HA-AFF1-overexpressing MSCs abrogates the impairment of osteogenic differentiation. Moreover, we detect that AFF4 is enriched in the promoter region of ID1. AFF4 knockdown blunts the BRE luciferase activity, SP7 expression and ALP activity induced by BMP2 treatment. In conclusion, our data indicate that AFF1 and AFF4 differentially regulate the osteogenic differentiation of human MSCs. | AFF1 and AFF4 differentially regulate the osteogenic differentiation of human MSCs |
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"28774": 0.17759032547473907, "28873": 0.08154398202896118, "28915": 0.9776504039764404, "29160": 0.8649974465370178, "29166": 0.4512746334075928, "29248": 0.0058422754518687725, "29299": 0.07793712615966797, "29327": 0.055094651877880096, "29458": 0.7665573358535767, "29610": 0.1930064558982849} | 25028913 | BACKGROUND In patients with unstable coronary artery disease, there is a relation between the short-term risk of death and blood levels of troponin T (a marker of myocardial damage) and C-reactive protein and fibrinogen (markers of inflammation). Using information obtained during an extension of the follow-up period in the Fragmin during Instability in Coronary Artery Disease trial, we evaluated the usefulness of troponin T, C-reactive protein, and fibrinogen levels and other indicators of risk as predictors of the long-term risk of death from cardiac causes. METHODS Levels of C-reactive protein and fibrinogen at enrollment and the maximal level of troponin T during the first 24 hours after enrollment were analyzed in 917 patients included in a clinical trial of low-molecular-weight heparin in unstable coronary artery disease. The patients were followed for a mean of 37.0 months (range, 1.6 to 50.6). RESULTS During follow-up, 1.2 percent of the 173 patients with maximal blood troponin T levels of less than 0.06 microg per liter died of cardiac causes, as compared with 8.7 percent of the 367 patients with levels of 0.06 to 0.59 microg per liter and 15.4 percent of the 377 patients with levels of at least 0.60 microg per liter (P=0.007 and P=0.001, respectively). The rates of death from cardiac causes were 5.7 percent among the 314 patients with blood C-reactive protein levels of less than 2 mg per liter, 7.8 percent among the 294 with levels of 2 to 10 mg per liter, and 16.5 percent among the 309 with levels of more than 10 mg per liter (P=0.29 and P=0.001, respectively). The rates of death from cardiac causes were 5.4 percent among the 314 patients with blood fibrinogen levels of less than 3.4 g per liter, 12.0 percent among the 300 with levels of 3.4 to 3.9 g per liter, and 12.9 percent among the 303 with levels of at least 4.0 g per liter (P=0.004 and P=0.69, respectively). In a multivariate analysis, levels of troponin T and C-reactive protein were independent predictors of the risk of death from cardiac causes. CONCLUSIONS In unstable coronary artery disease, elevated levels of troponin T and C-reactive protein are strongly related to the long-term risk of death from cardiac causes. These markers are independent risk factors, and their effects are additive with respect to each other and other clinical indicators of risk. | Markers of myocardial damage and inflammation in relation to long-term mortality in unstable coronary artery disease. FRISC Study Group. Fragmin during Instability in Coronary Artery Disease. |
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1.5280922651290894, "28424": 0.04487626627087593, "28699": 0.981317400932312, "28848": 0.2659635543823242, "28976": 0.4067663550376892, "29060": 0.2983669638633728, "29237": 0.08871890604496002, "29491": 1.2627575397491455} | 25036988 | Nuclear lamin B1 (LMNB1) constitutes one of the major structural proteins in the lamina mesh. We silenced the expression of LMNB1 by RNA interference in the colon cancer cell line DLD-1 and showed a dramatic redistribution of H3K27me3 from the periphery to a more homogeneous nuclear dispersion. In addition, we observed telomere attrition and an increased frequency of micronuclei and nuclear blebs. By 3D-FISH analyses, we demonstrated that the volume and surface of chromosome territories were significantly larger in LMNB1-depleted cells, suggesting that LMNB1 is required to maintain chromatin condensation in interphase nuclei. These changes led to a prolonged S phase due to activation of Chk1. Finally, silencing of LMNB1 resulted in extensive changes in alternative splicing of multiple genes and in a higher number of enlarged nuclear speckles. Taken together, our results suggest a mechanistic role of the nuclear lamina in the organization of chromosome territories, maintenance of genome integrity and proper gene splicing. | Loss of lamin B1 results in prolongation of S phase and decondensation of chromosome territories. |
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0.15610189735889435} | 25041967 | Human artificial chromosomes have been used to model requirements for human chromosome segregation and to explore the nature of sequences competent for centromere function. Normal human centromeres require specialized chromatin that consists of alpha satellite DNA complexed with epigenetically modified histones and centromere-specific proteins. While several types of alpha satellite DNA have been used to assemble de novo centromeres in artificial chromosome assays, the extent to which they fully recapitulate normal centromere function has not been explored. Here, we have used two kinds of alpha satellite DNA, DXZ1 (from the X chromosome) and D17Z1 (from chromosome 17), to generate human artificial chromosomes. Although artificial chromosomes are mitotically stable over many months in culture, when we examined their segregation in individual cell divisions using an anaphase assay, artificial chromosomes exhibited more segregation errors than natural human chromosomes (P < 0.001). Naturally occurring, but abnormal small ring chromosomes derived from chromosome 17 and the X chromosome also missegregate more than normal chromosomes, implicating overall chromosome size and/or structure in the fidelity of chromosome segregation. As different artificial chromosomes missegregate over a fivefold range, the data suggest that variable centromeric DNA content and/or epigenetic assembly can influence the mitotic behavior of artificial chromosomes. | Human artificial chromosomes with alpha satellite-based de novo centromeres show increased frequency of nondisjunction and anaphase lag. |
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0.19220098853111267, "28154": 0.1477125883102417, "28621": 1.0172666311264038, "28691": 0.2018241584300995, "28739": 0.25694093108177185, "28788": 0.401551216840744, "28873": 0.603290855884552, "28896": 1.0933903455734253, "29170": 0.32764431834220886, "29290": 0.42416930198669434, "29490": 0.09050461649894714} | 25045244 | Our previous studies in volunteers immunized with Salmonella enterica serovar Typhi (S. Typhi) have suggested an important role for CD8+ T cells in host defense. In this study we describe a novel subset of nonclassical human HLA-E-restricted S. Typhi-specific CD8+ T cells derived from PBMC of Ty21a typhoid vaccinees. CD3+CD8+CD4-CD56- T cells effectively killed S. Typhi-infected targets regardless of whether they share classical HLA class I molecules with them, by a FAS-independent, granule-dependent mechanism, as evidenced by induction of granzyme B release and the blocking effects of concanamycin and strontium ions. The expression of HLA-E Ags, but not CD1-a, -b, or -c, on the membrane of S. Typhi-infected targets rendered them susceptible to lysis. Moreover, anti-HLA-E Abs partially blocked these responses. We also demonstrated that presentation of S. Typhi Ags via HLA-E could stimulate IFN-gamma production. Increases in the net frequency of IFN-gamma spot-forming cells were observed in the presence of targets coated with peptides that contain S. Typhi GroEL HLA-E binding motifs. These results demonstrate that HLA-E binds nonamer peptides derived from bacterial proteins and trigger CD8+-mediated lysis and IFN-gamma production when exposed to infected targets, raising the possibility that this novel effector mechanism might contribute to host defense against intracellular bacterial infections. | Identification of a human HLA-E-restricted CD8+ T cell subset in volunteers immunized with Salmonella enterica serovar Typhi strain Ty21a typhoid vaccine. |
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SETTING Hlabisa health district, KwaZulu-Natal, South Africa. METHODS An economic analysis comparing the current tuberculosis management strategy in Hlabisa with three alternative strategies (the Hlabisa strategy prior to 1991 based on hospitalisation, the national strategy and sanatorium care) in terms of costs to both health service and patient and of cost-effectiveness. RESULTS The current Hlabisa strategy was the most cost-effective (R3799 per patient cured), compared with R98307 for the strategy used prior to 1991, R9940 for the national strategy, and R11145 for sanatorium care. Between 71% and 88% of treatment costs lie with the health service, and hospitalisation (R119 per day) is the most expensive item. Prolonged hospitalisation is extremely expensive, but community care is cheaper (community clinic visit, R28; community health worker visit, R7). The total cost of supervising a patient in the community under the current Hlabisa strategy was R503, equivalent to 4.2 days in hospital. Drug costs (R157) are equivalent to just 1.3 days in hospital. CONCLUSION Cost to both health service and patient can be substantially reduced by using community-based directly observed therapy for tuberculosis, a strategy that is cheap and cost-effective in Hlabisa. These findings have important national implications, supporting the goals of the new tuberculosis control programme. | Costs and cost-effectiveness of alternative tuberculosis management strategies in South Africa--implications for policy. |
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"24940": 0.3615458607673645, "25006": 0.43053874373435974, "25219": 0.052318159490823746, "25502": 0.5495203733444214, "25852": 0.09317722171545029, "26014": 0.06337817758321762, "26089": 0.0174254160374403, "26305": 0.306306391954422, "26402": 0.0317181795835495, "26721": 0.6054253578186035, "26976": 0.006812678650021553, "27651": 0.06337817758321762, "27753": 0.3070250153541565, "27854": 0.09672962874174118, "27891": 0.7463917136192322, "27929": 0.18329764902591705, "28046": 0.151916041970253, "28156": 0.5800528526306152, "28268": 0.1384023278951645, "28518": 0.018384648486971855, "29490": 0.3464667797088623} | 25050364 | OBJECTIVE The proinflammatory cytokine interleukin-18 (IL-18) putatively modulates food intake and energy metabolism, but the effects of IL-18 in high-fat diet fed animals are unknown. Whether IL-18 alters basal metabolic rate or metabolic processes of living is unknown. Here, we tested the hypothesis that IL-18 modulates weight gain, energy intake, whole-body energy expenditure, and utilization of lipid as a fuel substrate in high-fat diet fed mice. METHODS Food intake, whole-body metabolism, and motor activity of IL-18 knockout mice were compared to those of wildtype littermates; anorectic effects of intracerebroventricular IL-18 administration were compared between IL-18 receptor knockout, IL-18/IL-18R knockout and wildtype mice. RESULTS Chow-reared IL-18 knockout mice were overweight at 6 months of age and then gained excess weight on both low-fat and high-fat diets, ate more high-fat diet, and showed reduced whole-body energy expenditure and increased respiratory exchange ratios. Reductions in energy expenditure of IL-18 knockout mice were seen across fasting vs. feeding conditions, low- vs. high-fat diets, high vs. low levels of physical activity and times of day, suggesting actions on basal metabolic rate. The circadian amplitude of energy expenditure, but not respiratory exchange ratio, food intake, or motor activity, also was blunted in IL-18 knockout mice. Central IL-18 administration reduced high-fat diet intake in wildtype mice, but not in mice lacking the IL-18 receptor. CONCLUSION The loss-of-function results support the hypothesis that endogenous IL-18 suppresses appetite and promote energy expenditure and lipid fuel substrate utilization not only during sickness, but also in healthy adults consuming high-fat diets. | Interleukin-18 null mutation increases weight and food intake and reduces energy expenditure and lipid substrate utilization in high-fat diet fed mice |
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"23737": 0.9500881433486938, "23777": 0.3241194784641266, "23824": 0.1619328260421753, "23874": 1.072225570678711, "23892": 0.06886265426874161, "23900": 0.03266380727291107, "24054": 0.11343330889940262, "24269": 0.10731173306703568, "24587": 0.0029254043474793434, "24759": 0.17922431230545044, "25194": 0.21530038118362427, "25409": 0.8658194541931152, "25468": 0.09050461649894714, "25714": 0.14349138736724854, "25952": 0.04207121208310127, "25969": 0.9650808572769165, "26243": 0.02316705882549286, "26305": 0.22001366317272186, "26402": 0.176772341132164, "26886": 0.175953671336174, "27144": 0.16607704758644104, "27321": 0.6941232681274414, "27854": 0.7057625651359558, "27881": 0.2918238639831543, "27969": 1.2889312505722046, "28086": 0.24171993136405945, "28522": 0.13670019805431366, "28625": 0.9783848524093628, "28691": 0.08692999184131622, "28788": 0.04953393340110779, "28848": 0.7445381283760071, "29290": 0.23015019297599792, "29480": 0.9463045597076416} | 25050969 | Since Notch signaling plays a critical role in stem cells and oncogenesis, we hypothesized that Notch signaling might play roles in cancer stem cells and cancer cells with a stem cell phenotype. In this study, we accessed potential functions of the Notch pathway in the formation of cancer stem cells using human glioma. Using RT-PCR, we found that most human astrogliomas of different grades expressed moderate to high level of Notch receptors and ligands. mRNA of Hes5 but not Hes1, both of which are major downstream molecules of the Notch pathway, was also detected. In human glioma cell lines BT325, U251, SHG-44, and U87, mRNA encoding different types of Notch receptors were detected, but active form of Notch1 (NIC) was only detected in SHG-44 and U87 by Western blot. Interestingly, proliferation of these two glioma cell lines appeared faster than that of the other two lines in which NIC was not detected. We have over-expressed NIC of Notch1 in SHG-44 cells by constitutive transfection to evaluate the effects of Notch signaling on glioma cells. Our results showed that over-expression of NIC in SHG-44 cells promoted the growth and the colony-forming activity of SHG-44 cells. Interestingly, over-expression of NIC increased the formation neurosphere-like colonies in the presence of growth factors. These colonies expressed nestin, and could be induced to cells expressing neuron-, astrocyte-, or oligodendrocyte-specific markers, consistent with phenotypes of neural stem cells. These data suggest that Notch signaling promote the formation of cancer stem cell-like cells in human glioma. | Notch activation promotes cell proliferation and the formation of neural stem cell-like colonies in human glioma cells |
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Animal models, and more specifically rodent models, have been extensively used and have contributed greatly to the development and establishment of a wide range of translational approaches aiming to regenerate the bone tissue. In this regard, the calvarial defect model has found great application in basic and applied research, nonetheless the controversial rationalization for the use of critical size defects - defects that are unable to report spontaneous healing - or subcritical size defects in the proposed applications. Accordingly, this work aims to review the advantages and limitations of the use of rodent models in biomedical bone-related research, emphasizing the problematic issues of the use of calvarial critical and subcritical size defects. Additionally, surgical protocols for the establishment of both defects in rat calvarial bone, as well as the description and exemplification of the most frequently used techniques to access the bone tissue repair, are portrayed. | Rodent models in bone-related research: the relevance of calvarial defects in the assessment of bone regeneration strategies. |
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"26775": 0.6212902665138245, "26835": 1.0158531665802002, "27144": 0.23402166366577148, "27325": 0.33675122261047363, "27354": 0.4556184411048889, "27631": 0.07884006202220917, "27811": 0.18248429894447327, "28406": 0.9842413663864136, "28667": 0.5696102976799011, "29090": 0.20102575421333313, "29237": 0.23787821829319, "29290": 0.4950772523880005, "29458": 1.0423725843429565} | 25062868 | The differential transcriptional response of Mycobacterium tuberculosis to drugs and growth-inhibitory conditions was monitored to generate a data set of 430 microarray profiles. Unbiased grouping of these profiles independently clustered agents of known mechanism of action accurately and was successful at predicting the mechanism of action of several unknown agents. These predictions were validated biochemically for two agents of previously uncategorized mechanism, pyridoacridones and phenothiazines. Analysis of this data set further revealed 150 underlying clusters of coordinately regulated genes offering the first glimpse at the full metabolic potential of this organism. A signature subset of these gene clusters was sufficient to classify all known agents as to mechanism of action. Transcriptional profiling of both crude and purified natural products can provide critical information on both mechanism and detoxification prior to purification that can be used to guide the drug discovery process. Thus, the transcriptional profile generated by a crude marine natural product recapitulated the mechanistic prediction from the pure active component. The underlying gene clusters further provide fundamental insights into the metabolic response of bacteria to drug-induced stress and provide a rational basis for the selection of critical metabolic targets for screening for new agents with improved activity against this important human pathogen. | The transcriptional responses of Mycobacterium tuberculosis to inhibitors of metabolism: novel insights into drug mechanisms of action. |
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"26721": 0.8091925978660583, "26838": 0.7510106563568115, "26874": 0.1510767638683319, "27094": 0.1619328260421753, "27321": 0.5860490798950195, "27642": 0.7491656541824341, "28086": 1.3989098072052002, "28105": 0.2026219218969345, "28522": 0.8195732831954956, "28636": 0.6451379656791687, "28691": 0.21922965347766876, "28723": 0.02792670577764511, "28788": 0.38041436672210693, "29060": 0.14179791510105133} | 25068298 | Distribution and fine structure of macrophages were studied in 10 human embryos in the 6th and 7th week of gestation, 5.5 to 12 mm in crown-rump length. The yolk sac macrophages were found in the extravascular mesenchymal tissues and intravascular spaces long before the first appearance of bone marrow and lymphatic tissues in the embryos. In addition to the macrophages, the fibroblastic cells and the cells of erythropoietic series were also present in the extravascular space. The macrophages showed a variety of cellular structures suggesting transition from immature cell type with no heterophagolysosomes to mature cell type in phagocytosis. The mature macrophages avidly phagocytized the primitive erythroblasts and occasionally platelets. They were positively stained for lysosomal enzymes and were characterized by numerous pleomorphic heterophagolysosomes which exhibited various stages of digestion of phagocytized blood cells. The origin of intravascular macrophages may be in either migrated extravascular macrophages or phagocytic endothelial cells. The phagocytosis and degradation of erythroblasts appear to be one of the main functions of yolk sac macrophages. The presence of the macrophages in mitosis indicates their proliferation in situ. | Electron microscopic studies of macrophages in early human yolk sacs. |
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