tbuckley/cabot-search huggingface dataset:
Targeted Disruption of the<i>S1P</i><i>2</i>Sphingosine 1-Phosphate Receptor Gene Leads to Diffuse Large B-Cell Lymphoma Formation
Authors: Giorgio Cattoretti, Jonathan Mandelbaum, Nancy Lee, Alicia H. Chaves, Ashley M. Mahler, Amy Chadburn, Riccardo Dalla-Favera, Laura Pasqualucci, A. John MacLennan
Journal: Cancer Research (2009)

Abstract S1P2 sphingosine 1-phosphate receptor signaling can regulate proliferation, survival, morphology, and migration in many cell types in vitro. Here, we report that S1P2−/− mice develop clonal B-cell lymphomas with age, such that approximately half of the animals display this neoplasm by 1.5 to 2 years of age. Histologic, immunophenotypic, and molecular analyses revealed a uniform tumor phenotype with features of germinal center (GC)–derived diffuse large B-cell lymphoma (DLBCL). Tumor formation was preceded by increases in GC B cells and CD69+ T cells, as well as an increased formation of spontaneous GCs, suggesting that S1P2 loss may promote lymphomagenesis in part by disrupting GC B-cells homeostasis. With the sole exception of rare lung tumors, the effect of S1P2 gene disruption is remarkably restricted to DLBCL. In humans, 28 of 106 (26%) DLBCL samples were found to harbor multiple somatic mutations in the 5′ sequences of the S1P2 gene. Mutations displayed features resembling those generated by the IgV-associated somatic hypermutation mechanism, but were not detected at significant levels in normal GC B cells, indicating a tumor-associated aberrant function. Collectively, our data suggest that S1P2 signaling may play a critical role in suppressing DLBCL formation in vivo. The high incidence of DLBCL in S1P2−/− mice, its onset at old age, and the relative lack of other neoplasms identify these mice as a novel, and potentially valuable, model for this highly prevalent and aggressive human malignancy. [Cancer Res 2009;69(22):8686–92]
A Bayesian Approach for Fast and Accurate Gene Tree Reconstruction
Authors: M. D. Rasmussen, M. Kellis
Journal: Molecular Biology and Evolution (2010)

Recent sequencing and computing advances have enabled phylogenetic analyses to expand to both entire genomes and large clades, thus requiring more efficient and accurate methods designed specifically for the phylogenomic context. Here, we present SPIMAP, an efficient Bayesian method for reconstructing gene trees in the presence of a known species tree. We observe many improvements in reconstruction accuracy, achieved by modeling multiple aspects of evolution, including gene duplication and loss (DL) rates, speciation times, and correlated substitution rate variation across both species and loci. We have implemented and applied this method on two clades of fully sequenced species, 12 Drosophila and 16 fungal genomes as well as simulated phylogenies and find dramatic improvements in reconstruction accuracy as compared with the most popular existing methods, including those that take the species tree into account. We find that reconstruction inaccuracies of traditional phylogenetic methods overestimate the number of DL events by as much as 2–3-fold, whereas our method achieves significantly higher accuracy. We feel that the results and methods presented here will have many important implications for future investigations of gene evolution.
Abuse of people with dementia by family carers: representative cross sectional survey
Authors: C. Cooper, A. Selwood, M. Blanchard, Z. Walker, R. Blizard, G. Livingston
Journal: BMJ (2009)

<b>Objective</b> To determine the prevalence of abusive behaviours by family carers of people with dementia. <b>Design</b> Representative cross sectional survey <b>Setting</b> Community mental health teams in Essex and London. <b>Participants</b> 220 family carers of people newly referred to secondary psychiatric services with dementia who were living at home. <b>Main outcome measure</b> Psychological and physical abuse (revised modified conflict tactics scale). <b>Results</b> 115 (52%, 95% confidence interval 46% to 59%) carers reported some abusive behaviour and 74 (34%, 27% to 40%) reported important levels of abuse. Verbal abuse was most commonly reported. Only three (1.4%) carers reported occasional physical abuse. <b>Conclusions</b> Abusive behaviour by family carers towards people with dementia is common, with a third reporting important levels of abuse and half some abusive behaviour. We found few cases of physical or frequent abuse, although those with the most abusive behaviour may have been reluctant to report it.
Effect of breast milk and weaning on epithelial growth of the small intestine in humans
Authors: A G Cummins
Journal: Gut (2002)

Breast feeding and weaning are important physiologically significant luminal events that influence the growth of the small intestine in humans. A variety of factors including genetic preprogramming, systemic and local hormones, and permissive factors contribute and modulate intestinal growth. Here, we offer a view that integrates some of these factors, especially those relating to breast feeding and weaning.
Rethinking the “Diseases of Affluence” Paradigm: Global Patterns of Nutritional Risks in Relation to Economic Development
Authors: Majid Ezzati, Stephen Vander Hoorn, Carlene M. M Lawes, Rachel Leach, W. Philip T James, Alan D Lopez, Anthony Rodgers, Christopher J. L Murray
Journal: PLoS Medicine (2005)

Background Cardiovascular diseases and their nutritional risk factors—including overweight and obesity, elevated blood pressure, and cholesterol—are among the leading causes of global mortality and morbidity, and have been predicted to rise with economic development. Methods and Findings We examined age-standardized mean population levels of body mass index (BMI), systolic blood pressure, and total cholesterol in relation to national income, food share of household expenditure, and urbanization in a cross-country analysis. Data were from a total of over 100 countries and were obtained from systematic reviews of published literature, and from national and international health agencies. BMI and cholesterol increased rapidly in relation to national income, then flattened, and eventually declined. BMI increased most rapidly until an income of about I$5,000 (international dollars) and peaked at about I$12,500 for females and I$17,000 for males. Cholesterol's point of inflection and peak were at higher income levels than those of BMI (about I$8,000 and I$18,000, respectively). There was an inverse relationship between BMI/cholesterol and the food share of household expenditure, and a positive relationship with proportion of population in urban areas. Mean population blood pressure was not correlated or only weakly correlated with the economic factors considered, or with cholesterol and BMI. Conclusions When considered together with evidence on shifts in income–risk relationships within developed countries, the results indicate that cardiovascular disease risks are expected to systematically shift to low-income and middle-income countries and, together with the persistent burden of infectious diseases, further increase global health inequalities. Preventing obesity should be a priority from early stages of economic development, accompanied by population-level and personal interventions for blood pressure and cholesterol.
Pregnancy complications in women with polycystic ovary syndrome
Authors: Stefano Palomba, Marlieke A. de Wilde, Angela Falbo, Maria P.H. Koster, Giovanni Battista La Sala, Bart C.J.M. Fauser
Journal: Human Reproduction Update (2015)

The great majority of studies performed so far concerning women diagnosed with polycystic ovary syndrome (PCOS) have focused on diagnosis, menstrual cycle abnormalities, hirsutism and infertility. Although progress has been made in developing methods for achieving a pregnancy and reducing multiple gestations in women with PCOS, little attention has been paid to pregnancy complications and subsequent child outcomes. This review aims to summarize current knowledge regarding the clinical and pathophysiological features of pregnancy and children in women with PCOS. A literature search up to April 2015 was performed in PubMed, Medline, the Cochrane Library and Web of Science without language restriction. All articles were initially screened for title and abstract and full texts of eligible articles were subsequently selected. Systematic reviews with meta-analysis were initially included for each specific subject. Recent randomised controlled trials (RCTs), which were not included in the systematic reviews, were also included. In addition to evidence from meta-analyses or RCTs, we used non-randomized prospective, uncontrolled prospective, retrospective and experimental studies. When specific data for patients with PCOS were lacking, results from general population studies were reported. Women with PCOS exhibit a clinically significant increased risk of pregnancy complications compared with controls. Data which were not adjusted for BMI or other confounders demonstrated in PCOS a 3–4-fold increased risk of pregnancy-induced hypertension and pre-eclampsia, a 3-fold increased risk of gestational diabetes and 2-fold higher chance for premature delivery. Features characteristic of PCOS, such as hyperandrogenism, obesity, insulin resistance and metabolic abnormalities, may contribute to the increased risk of obstetric and neonatal complications. Limited available data suggest that offspring of women with PCOS have an increased risk for future metabolic and reproductive dysfunction. Underlying pathophysiological mechanisms of pregnancy complications along with its association with health of offspring remain uncertain. To date, the strategies for prevention and management of pregnancy complications in women with PCOS, and whether long-term health of these women is influenced, and to what extent, by pregnancy and/or pregnancy complications, remain to be elucidated. Women with PCOS show an increased risk of pregnancy complications. Heterogeneous aetiological factors involved in PCOS and associated co-morbidities may all be involved in compromised pregnancy and child outcomes. In women with PCOS, a possible relationship with genetic, environmental, clinical and biochemical factors involved in this complex condition, as well as with pregnancy complications and long-term health for both mother and child, remains to be established.
Testing pitfalls and summary of guidance in lipid management
Authors: W Stuart A Smellie
Journal: BMJ (2006)

One of the difficulties in addressing the large differences in use of laboratory tests1 is to produce robust protocols, supported by high level evidence, for the use of these tests. A working group has been established to improve the knowledge base in laboratory medicine and is working with Sir Muir Gray, director of clinical knowledge, process and patient safety for the National Programme for Information Technology.2 The initiative has brought together contributions from a range of professional associations and clinical authors to improve knowledge in the use of laboratory testing. It is collating answers to about 100 frequently asked questions in primary care on the use of laboratory tests and is presenting these through a range of media, using a standardised literature search targeted towards clinical guidelines and evidence based reviews. The complete question-answer sets are being developed into prompts, reminders, and alerts to help doctors and nurses while they are treating patients. This series of articles has been constructed around relevant clinical cases which illustrate some of the problems that can arise in using, or not using, laboratory tests, linked to the guidance points obtained from these answers.

The key points are a synthesis of existing guidelines on the subjects concerned, and in most cases originate from the consensus of national or international experts. They are “the best we can get” at present, although the answering process has revealed questions that justify further research and could have a large impact on policies for use of tests. To enrich this debate, guidance is accompanied by evidence notes highlighting the strengths or weaknesses of the evidence base supporting the guidance.

This article presents and discusses two typical cases seen in a district hospital lipid clinic. Laboratories differ in the profiles of tests they offer, and some will add tests …
INTESTINAL OBSTRUCTION PRODUCED BY AN ENORMOUSLY DISTENDED STOMACH
Authors: A. E. Maylard
Journal: BMJ (1909)

<ovenient, and paallel to the whole length of the skin mcision.Through this opening the whole of the upper .aiodoencan be explored, and if operation on lateral organs is deemed advisable, the horizontal limb is then added.The best point for dividing the rectus is at its umbilical intersection, but it may be divided anywhere.This intersection is readily exposed by prolonging the vertical incision if necessary, and from the lower end of -this a curved incision is made upwards and outwards to the lowest part of the costal margin.This divides slkin and superficial fascia only.The muscle with the skin and anterior sheath is now raised up with the left hand, and the whole cut straight outwards through the middle of the fibrous intersection till the whole thickness of the rectus is divided.The deep epigastric, or a branch, may bleed and require securing.the posterior sheath 1is -divided i in.higher up for ease in suturing later.In very fa subjects the ends of the skin incisions are prolonged and gradually shallowed out at their ends.This gives considerably more room, and does not weaken the cieatrix in the least.When turned up the base of this ilap lies 'along Kocher's incision.The costal cartilages ~can be cut from the peritoneal side if ncessary for opera- tions on the spleen or cardiac end of the stomach.With 'the sandbag under the patient excellAt exposure is got, and the edges of the opening are not too rigid.Only one
Hospital Electrical Hazards Revisited
Authors: Harvey Salomon
Journal: New England Journal of Medicine (1972)

Two or three years ago there was an outburst of public and professional concern regarding electrical safety in hospitals. General agreement was voiced that the problem was increasing as more and more susceptible patients were being placed in electrically proliferating environments, but the extent of the problem was never reliably measured.One of the first estimates of the electrical hazard in hospitals was offered by a noted surgeon, who quoted a figure from actuarial sources of 1200 deaths annually in association with medical electronic equipment. This was followed by the statement of a consumer protectionist, who said more than 5000 . . .
Down-regulation of SREBP-1c is associated with the development of burned-out NASH
Authors: Tadanobu Nagaya, Naoki Tanaka, Takefumi Suzuki, Kenji Sano, Akira Horiuchi, Michiharu Komatsu, Takero Nakajima, Tomoko Nishizawa, Satoru Joshita, Takeji Umemura, Tetsuya Ichijo, Akihiro Matsumoto, Kaname Yoshizawa, Jun Nakayama, Eiji Tanaka, Toshifumi Aoyama
Journal: Journal of Hepatology (2010)
Loss of Heterozygosity of Chromosome 3 Detected with Single Nucleotide Polymorphisms Is Superior to Monosomy 3 for Predicting Metastasis in Uveal Melanoma
Authors: Michael D. Onken, Lori A. Worley, Erica Person, Devron H. Char, Anne M. Bowcock, J. William Harbour
Journal: Clinical Cancer Research (2007)

Abstract Purpose: Loss of chromosome 3 is strongly associated with metastasis in uveal melanoma and has been proposed as the basis for clinical prognostic testing. It is not known whether techniques that identify loss of heterozygosity for chromosome 3 predict metastasis more accurately than those that detect only numerical loss of chromosome 3 (monosomy 3). Experimental Design: Fifty-three uveal melanomas were analyzed by 28 single nucleotide polymorphisms (SNP) across chromosome 3. SNP was compared with fluorescence in situ hybridization (FISH) and array-based comparative genomic hybridization (aCGH) for metastasis prediction by sensitivity, specificity, and Kaplan-Meier survival analysis, using our validated gene expression-based classifier as a reference standard. Results: By Kaplan-Meier analysis, only the gene expression-based classifier (P = 0.001) and SNP-based detection of loss of heterozygosity for chromosome 3 (P = 0.04) were significantly associated with metastasis. Sensitivity and specificity were 95.2% and 80.8%, respectively, for SNP, 77.8% and 64.7%, respectively, for FISH, and 85.0% and 72.0%, respectively, for aCGH. Isodisomy 3 was identified by SNP but undetected by aCGH and FISH in three tumors. Conclusions: Prognostic tests based on SNP platforms, which detect both chromosomal homologues and their subregions, may be superior to techniques that only detect changes in chromosome number. These observations could have important implications for efforts to detect genetic alterations in cancer genomes with CGH-based approaches.
Epinephrine plasma metabolic clearance rates and physiologic thresholds for metabolic and hemodynamic actions in man.
Authors: W E Clutter, D M Bier, S D Shah, P E Cryer
Journal: Journal of Clinical Investigation (1980)

To determine the plasma epinephrine thresholds for its metabolic and hemodynamic actions and plasma epinephrine metabolic clearance rates, 60-min intravenous epinephrine infusions at nominal rates of 0.1, 0.5, 1.0, 2.5, and 5.0 microgram/min were performed in each of six normal human subjects. These 30 infusions resulted in steady-state plasma epinephrine concentrations ranging from 24 to 1,020 pg/ml. Plasma epinephrine thresholds were 50-100 pg/ml for increments in heart rate, 75-125 pg/ml for increments in blood glycerol and systolic blood pressure, 150-200 pg/ml for increments in plasma glucose (the resultant of increments in glucose production and decrements in glucose clearance), blood lactate, blood beta-hydroxybutyrate, and diastolic blood pressure, and greater than 400 pg/ml for early decrements in plasma insulin. Changes in blood alanine, plasma glucagon, plasma growth hormone, and plasma cortisol were not detected. At steady-state plasma epinephrine concentrations of 24-74 pg/ml, values overlapping the basal normal range, the mean (+/-SE) plasma metabolic clearance rate of epinephrine was 52 +/- 4 ml x min-1 x kg-1; this value rose to 89 +/- 6 ml x min-1 x kg-1 (P less than 0.01) at steady-state epinephrine concentrations of 90-1,020 pg/ml. We conclude that in human subjects: (a) the plasma epinephrine thresholds for its hemodynamic and metabolic actions lie within the physiologic range, (b) epinephrine and norepinephrine accelerate their own metabolic clearance, and (c) epinephrine is 10 times more potent than norepinephrine.
MACROPHAGE PLASMA MEMBRANE
Authors: Ralph L. Nachman, Barbara Ferris, James G. Hirsch
Journal: The Journal of Experimental Medicine (1971)

Rabbit alveolar macrophages were incubated in vitro with radioactive protein precursors. Plasma membranes were isolated from these cells, dissolved in phenol-urea-acetic acid, and separated by acrylamide gel electrophoresis. 3H-leucine was rapidly incorporated into membrane protein. The rate of labeling with 3H-leucine was markedly different from one protein band to another, indicating heterogeneous or multistep synthesis and assembly of proteins in the alveolar macrophage plasma membrane. Cells incubated with 3H-choline incorporated this compound into membrane lecithin. On gel electrophoresis the label derived from choline was located in the two bands migrating most rapidly towards the cathode. Studies on cells incubated with 3H-glucosamine revealed incorporation of label into two protein bands, one located near the origin and the other migrating rapidly towards the cathode. The in vitro techniques were also employed for pulse-chase studies to gain information on rate of turnover of macrophage plasma membrane proteins. This turnover rate was rapid, with a half-life of approximately 8 hr. The radioactivity disappeared from the several protein bands at the same rate, suggesting bulk removal of membrane rather than catabolism of the individual proteins in situ. Endocytosis seems a likely mechanism to account for a major part of the plasma membrane removal. Studies on the protein components of phagolysosomal membranes from cells which had been labeled with 3H-leucine revealed the presence of all of the major labeled protein bands characteristic of the plasma membrane except one, thus confirming the bulk interiorization of large segments or units of plasma membrane by endocytic processes.
The advisory process for anticancer drug regulation: a global perspective
Authors: A.T. Farrell, I. Papadouli, A. Hori, M. Harczy, B. Harrison, W. Asakura, M. Marty, R. Dagher, R. Pazdur
Journal: Annals of Oncology (2005)

PurposeThis paper summarizes the role of external advisors in oncology drug development and regulation from a global perspective.DesignRecently, representatives from the United States Food and Drug Administration, European Medicines Agency, the Japanese Pharmaceuticals and Medical Devices Agency, the Australian Therapeutic Goods Administration and Health Canada held a meeting in conjunction with the American Society of Clinical Oncology meeting. The role of external advisors in oncology drug development and regulation in each of these jurisdictions was presented and discussed.ResultsAll regulatory bodies described have experience with two forms of outside expertise: advice from individual experts and advice from a group of experts assembled as an advisory group. Regulatory jurisdictions use individual experts variably. In some regions, individual experts provide advice based on knowledge and experience during the drug development phase or in the planning phase for the submission of a drug registration package. In other regions, these individuals serve as external evaluators with the primary responsibility for the review of a clinical trials package submitted for drug registration. Advisory boards have been formalized in all jurisdictions discussed. Advisory boards have a role in discussing specific applications as well as broad policy issues. A common theme is a composition of a core panel of experts with augmentation by additional expertise as needed for consideration of specific scientific questions. In all jurisdictions, advisory board recommendations are not binding on the regulatory body.ConclusionsGlobal oncology drug development and registration involves the use of experts by regulatory authorities. The types of experts needed, the expert's role and the transparency of the advisory process reflect the individual needs in different regions.