173 research outputs found
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Nonconcordance between Clinical and Head CT Findings: The Specter of Overdiagnosis
Background:. It is unclear whether history and physical examination findings can predict abnormalities on head computed tomography (CT) believed to indicate increased risk of lumbar-puncture- (LP-) induced brain herniation. The objectives of this study were to (1) identify head CT findings felt to be associated with increased risk of brain herniation and (2) to assess the ability of history and physical examination to predict those findings. Methods:. Using a modified Delphi survey technique, an expert panel defined CT abnormalities felt to predict increased risk of LP-induced brain herniation. Presence of such findings on CT was compared with history and physical examination (H&P) variables in 47 patients. Results:. No H&P variable predicted “high-risk” CT; combining H&P variables to improve sensitivity led to extremely low specificity and still failed to identify all patients with high-risk CT. Conclusions:. “High-risk” CT is not uncommon in patients with clinical characteristics known to predict an absence of actual risk from LP, and thus it may not be clinically relevant. “Overdiagnosis” will be increasingly problematic as technological advances identify increasingly subtle deviations from “normal.
Indigenous knowledges and development: a postcolonial caution
As a result of the failure of formal top-down development, there has recently been increased interest in the possibilities of drawing upon the indigenous knowledges of those in the communities involved, in an attempt to produce more effective development strategies. The concept of indigenous knowledge calls for the inclusion of local voices and priorities, and promises empowerment through ownership of the process. However, there has been little critical examination of the ways in which indigenous knowledges have been included in the development process. Drawing upon postcolonial theory, this article suggests that indigenous knowledges are often drawn into development by both theorists and development institutions in a very limited way, failing to engage with other ways of perceiving development, and thus missing the possibility of devising more challenging alternatives
Dasatinib preferentially induces apoptosis by inhibiting Lyn kinase in nilotinib-resistant chronic myeloid leukemia cell line
Nilotinib is approved for treatment of newly diagnosed chronic myeloid leukemia (CML) and it is shown superiority over imatinib in first-line treatment for patients of CML. In this study, we established a nilotinib-resistant cell line, K562NR, and evaluated the resistance to nilotinib and efficacy of dasatinib. We found activation of Lyn plays a dominant role in survival of the nilotinib-resistant cell line. We found dasatinib induces the apoptosis of nilotinib-resistant cells and inhibits Lyn kinase activity. This novel nilotinib-resistant CML cell line may help to explore novel therapy for CML
Genetic heterogeneity of induced pluripotent stem cells: results from 24 clones derived from a single C57BL/6 mouse.
This is the final version of the article. It first appeared from PLOS via http://dx.doi.org/10.1371/journal.pone.0120585Induced pluripotent stem cells (iPSCs) have tremendous potential as a tool for disease modeling, drug testing, and other applications. Since the generation of iPSCs "captures" the genetic history of the individual cell that was reprogrammed, iPSC clones (even those derived from the same individual) would be expected to demonstrate genetic heterogeneity. To assess the degree of genetic heterogeneity, and to determine whether some cells are more genetically "fit" for reprogramming, we performed exome sequencing on 24 mouse iPSC clones derived from skin fibroblasts obtained from two different sites of the same 8-week-old C57BL/6J male mouse. While no differences in the coding regions were detected in the two parental fibroblast pools, each clone had a unique genetic signature with a wide range of heterogeneity observed among the individual clones: a total of 383 iPSC variants were validated for the 24 clones (mean 16.0/clone, range 0-45). Since these variants were all present in the vast majority of the cells in each clone (variant allele frequencies of 40-60% for heterozygous variants), they most likely preexisted in the individual cells that were reprogrammed, rather than being acquired during reprogramming or cell passaging. We then tested whether this genetic heterogeneity had functional consequences for hematopoietic development by generating hematopoietic progenitors in vitro and enumerating colony forming units (CFUs). While there was a range of hematopoietic potentials among the 24 clones, only one clone failed to differentiate into hematopoietic cells; however, it was able to form a teratoma, proving its pluripotent nature. Further, no specific association was found between the mutational spectrum and the hematopoietic potential of each iPSC clone. These data clearly highlight the genetic heterogeneity present within individual fibroblasts that is captured by iPSC generation, and suggest that most of the changes are random, and functionally benign.This work was supported by grants from the NIH (CA101937 and CA162086, to TJL, and HL116605, to JMK), the Barnes Jewish Hospital Foundation (00335-0505-02, to TJL), and the Burroughs Wellcome Fund (to JMK). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript
Dental management considerations for the patient with an acquired coagulopathy. Part 1: Coagulopathies from systemic disease
Current teaching suggests that many patients are at risk for prolonged bleeding during and following invasive dental procedures, due to an acquired coagulopathy from systemic disease and/or from medications. However, treatment standards for these patients often are the result of long-standing dogma with little or no scientific basis. The medical history is critical for the identification of patients potentially at risk for prolonged bleeding from dental treatment. Some time-honoured laboratory tests have little or no use in community dental practice. Loss of functioning hepatic, renal, or bone marrow tissue predisposes to acquired coagulopathies through different mechanisms, but the relationship to oral haemostasis is poorly understood. Given the lack of established, science-based standards, proper dental management requires an understanding of certain principles of pathophysiology for these medical conditions and a few standard laboratory tests. Making changes in anticoagulant drug regimens are often unwarranted and/or expensive, and can put patients at far greater risk for morbidity and mortality than the unlikely outcome of postoperative bleeding. It should be recognised that prolonged bleeding is a rare event following invasive dental procedures, and therefore the vast majority of patients with suspected acquired coagulopathies are best managed in the community practice setting
Support for UNRWA's survival
The United Nations Relief and Works Agency for Palestine Refugees in the Near East (UNRWA) provides life-saving humanitarian aid for 5·4 million Palestine refugees now entering their eighth decade of statelessness and conflict. About a third of Palestine refugees still live in 58 recognised camps. UNRWA operates 702 schools and 144 health centres, some of which are affected by the ongoing humanitarian disasters in Syria and the Gaza Strip. It has dramatically reduced the prevalence of infectious diseases, mortality, and illiteracy. Its social services include rebuilding infrastructure and homes that have been destroyed by conflict and providing cash assistance and micro-finance loans for Palestinians whose rights are curtailed and who are denied the right of return to their homeland
Wealthy and healthy? New evidence on the relationship between wealth and HIV vulnerability in Tanzania
Using AIS/DHS data for Tanzania in 2003-4, 2007-8 and 2011-12 and borrowing from the methodology used in Parkhurst (2010) we analyse the changing relationship between wealth and HIV prevalence in Tanzania. Findings are tabulated, graphed and discussed.
We find the relationship is multifaceted and dynamic: women are disproportionately affected in all wealth quintiles and experience a stronger ‘wealth effect’; some groups experience an increase in prevalence even as population prevalence declines. Relative wealth and poverty are associated with increased prevalence, suggesting that structural drivers create a variety of risk situations – as well as protective factors – affecting different groups.
We also consider data on testing refusals: wealthier men were consistently more likely to decline testing. Continuing to unpack this complex and shifting relationship is necessary in order to fully understand the structural drivers of HIV transmission and access of testing services, enabling the formulation of appropriate policy responses
Compensatory Development and Costs of Plasticity: Larval Responses to Desiccated Conspecifics
Understanding constraints on phenotypic plasticity is central to explaining its evolution and the evolution of phenotypes in general, yet there is an ongoing debate on the classification and relationships among types of constraints. Since plasticity is often a developmental process, studies that consider the ontogeny of traits and their developmental mechanisms are beneficial. We manipulated the timing and reliability of cues perceived by fire salamander larvae for the future desiccation of their ephemeral pools to determine whether flexibility in developmental rates is constrained to early ontogeny. We hypothesized that higher rates of development, and particularly compensation for contradictory cues, would incur greater endogenous costs. We found that larvae respond early in ontogeny to dried conspecifics as a cue for future desiccation, but can fully compensate for this response in case more reliable but contradictory cues are later perceived. Patterns of mortality suggested that endogenous costs may depend on instantaneous rates of development, and revealed asymmetrical costs of compensatory development between false positive and false negative early information. Based on the results, we suggest a simple model of costs of development that implies a tradeoff between production costs of plasticity and phenotype-environment mismatch costs, which may potentially underlie the phenomenon of ontogenetic windows constraining plasticity
Patterns and correlates of tobacco control behavior among american association of pediatric dentistry members: a cross-sectional national study
<p>Abstract</p> <p>Background</p> <p>To determine the tobacco-related knowledge, attitudes, and practice behaviors among US pediatric dentists.</p> <p>Methods</p> <p>A survey was conducted in 1998 among a national, random sample of 1500 American Academy of Pediatric Dentistry members. Chi-square tests and logistic regression with odds ratios (ORs) and 95% confidence intervals assessed factors related to pediatric dentists' tobacco control behaviors.</p> <p>Results</p> <p>Response was 65% for the survey. Only 12% of respondents had prior tobacco prevention/cessation training. Of those untrained, 70% were willing to be trained. Less than two-thirds correctly answered any of four tobacco-related knowledge items. Over one-half agreed pediatric dentists should engage in tobacco control behaviors, but identified patient resistance as a barrier. About 24% of respondents reported always/often asking their adolescent patients about tobacco use; 73% reported always/often advising known tobacco users to quit; and 37% of respondents always/often assisting with stopping tobacco use. Feeling prepared to perform tobacco control behaviors (ORs = 1.9–2.8), a more positive attitude score (4 points) from 11 tobacco-related items (ORs = 1.5–1.8), and a higher statewide tobacco use prevalence significantly predicted performance of tobacco control behaviors.</p> <p>Conclusion</p> <p>Findings suggest thatraining programs on tobacco use and dependence treatment in the pediatric dental setting may be needed to promote tobacco control behaviors for adolescent patients.</p
Integrated genomic analyses of ovarian carcinoma
A catalogue of molecular aberrations that cause ovarian cancer is critical for developing and deploying therapies that will improve patients’ lives. The Cancer Genome Atlas project has analysed messenger RNA expression, microRNA expression, promoter methylation and DNA copy number in 489 high-grade serous ovarian adenocarcinomas and the DNA sequences of exons from coding genes in 316 of these tumours. Here we report that high-grade serous ovarian cancer is characterized by TP53 mutations in almost all tumours (96%); low prevalence but statistically recurrent somatic mutations in nine further genes including NF1, BRCA1, BRCA2, RB1 and CDK12; 113 significant focal DNA copy number aberrations; and promoter methylation events involving 168 genes. Analyses delineated four ovarian cancer transcriptional subtypes, three microRNA subtypes, four promoter methylation subtypes and a transcriptional signature associated with survival duration, and shed new light on the impact that tumours with BRCA1/2 (BRCA1 or BRCA2) and CCNE1 aberrations have on survival. Pathway analyses suggested that homologous recombination is defective in about half of the tumours analysed, and that NOTCH and FOXM1 signalling are involved in serous ovarian cancer pathophysiology.National Institutes of Health (U.S.) (Grant U54HG003067)National Institutes of Health (U.S.) (Grant U54HG003273)National Institutes of Health (U.S.) (Grant U54HG003079)National Institutes of Health (U.S.) (Grant U24CA126543)National Institutes of Health (U.S.) (Grant U24CA126544)National Institutes of Health (U.S.) (Grant U24CA126546)National Institutes of Health (U.S.) (Grant U24CA126551)National Institutes of Health (U.S.) (Grant U24CA126554)National Institutes of Health (U.S.) (Grant U24CA126561)National Institutes of Health (U.S.) (Grant U24CA126563)National Institutes of Health (U.S.) (Grant U24CA143882)National Institutes of Health (U.S.) (Grant U24CA143731)National Institutes of Health (U.S.) (Grant U24CA143835)National Institutes of Health (U.S.) (Grant U24CA143845)National Institutes of Health (U.S.) (Grant U24CA143858)National Institutes of Health (U.S.) (Grant U24CA144025)National Institutes of Health (U.S.) (Grant U24CA143866)National Institutes of Health (U.S.) (Grant U24CA143867)National Institutes of Health (U.S.) (Grant U24CA143848)National Institutes of Health (U.S.) (Grant U24CA143843)National Institutes of Health (U.S.) (Grant R21CA135877
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