tbuckley/cabot-search huggingface dataset:
Cholesterol synthesis and high density lipoprotein uptake are regulated independently in rat small intestinal epithelium.
Authors: C Lutton, G Champarnaud
Journal: Gut (1994)

The rates of high density lipoprotein HDL uptake and cholesterol synthesis were compared in the normocholesterolaemic (SW) and genetically hypercholesterolaemic (RICO) rat intestine. The RICO rat has a hyperintestinal cholesterol synthesis. 14C sucrose, a marker which becomes irreversibly entrapped within the cells, was used to measure total rat HDL uptake over 24 hours in the various cells of the small intestinal mucosa. The rates of sterol synthesis were estimated in vivo with 1-14C acetate, as previously validated. The rates of HDL uptake in the upper villus cells were similar along the length of the small intestine in both types of rat, but the rates of sterol synthesis varied up to eightfold. When the mucosal epithelium was divided along the villus/crypt axis, HDL uptake increased two to threefold and cholesterol synthesis two to fivefold in the upper villus compared with the crypt cells in both SW and RICO rats. The high cholesterogenesis in the mucosal cells of the RICO rat is not related to a modified HDL cholesterol uptake. Thus, cholesterol synthesis and HDL uptake seem to be regulated independently in the rat small intestinal mucosa.
<i>MSH6</i> Mutations Arise in Glioblastomas during Temozolomide Therapy and Mediate Temozolomide Resistance
Authors: Stephen Yip, Jiangyong Miao, Daniel P. Cahill, A. John Iafrate, Ken Aldape, Catherine L. Nutt, David N. Louis
Journal: Clinical Cancer Research (2009)

Abstract Purpose: Over the past few years, the alkylating agent temozolomide has become the standard-of-care therapy for patients with glioblastoma, the most common brain tumor. Recently, large-scale cancer genome sequencing efforts have identified a hypermutation phenotype and inactivating MSH6 mismatch repair gene mutations in recurrent, post-temozolomide glioblastomas, particularly those growing more rapidly during temozolomide treatment. This study aimed to clarify the timing and role of MSH6 mutations in mediating glioblastoma temozolomide resistance. Experimental Design: MSH6 sequence and microsatellite instability (MSI) status were determined in matched prechemotherapy and postchemotherapy glioblastomas identified by The Cancer Genome Atlas (TCGA) as having posttreatment MSH6 mutations. Temozolomide-resistant lines were derived in vitro through selective growth under temozolomide, and the MSH6 gene was sequenced in resistant clones. The role of MSH6 inactivation in mediating resistance was explored using lentiviral short hairpin RNA knockdown and MSH6 reconstitution. Results: MSH6 mutations were confirmed in posttreatment TCGA glioblastomas but absent in matched pretreatment tumors. The posttreatment hypermutation phenotype displayed a signature bias toward CpC transitions and was not associated with MSI. In vitro modeling through exposure of an MSH6 wild-type glioblastoma line to temozolomide resulted in resistant clones; one clone showed an MSH6 mutation, Thr1219Ile, that had been independently noted in two treated TCGA glioblastomas. Knockdown of MSH6 in the glioblastoma line U251 increased resistance to temozolomide cytotoxicity and reconstitution restored cytotoxicity in MSH6-null glioma cells. Conclusions: MSH6 mutations are selected in glioblastomas during temozolomide therapy both in vitro and in vivo and are causally associated with temozolomide resistance.
Adjunct prednisolone therapy does not improve survival in HIV-associated tuberculous pleurisy
Authors: R Johns
Journal: Thorax (2004)

▴ Elliott AM, Luzze H, Quigley MA, et al . A randomized, double-blind, placebo-controlled trial of the use of prednisolone as an adjunct to treatment in HIV-1-associated pleural tuberculosis. J Infect Dis2004;190:869–78 [OpenUrl][1][Abstract/FREE Full Text][2] Glucocorticoids reduce excessive inflammation in pleural tuberculosis and have been shown to hasten resolution in HIV negative patients. Active tuberculosis can speed progression of HIV infection since HIV replicates more rapidly in activated lymphocytes. Given that prednisolone therapy is associated with reduced immune activation in HIV positive subjects, the … [1]: {openurl}?query=rft.jtitle%253DJ%2BInfect%2BDis%26rft_id%253Dinfo%253Adoi%252F10.1086%252F422257%26rft_id%253Dinfo%253Apmid%252F15295690%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [2]: /lookup/ijlink?linkType=ABST&journalCode=jinfdis&resid=190/5/869&atom=%2Fthoraxjnl%2F59%2F12%2F1031.atom
Use of the Thyroid Hormone Analogue Eprotirome in Statin-Treated Dyslipidemia
Authors: Paul W. Ladenson, Jens D. Kristensen, E. Chester Ridgway, Anders G. Olsson, Bo Carlsson, Irwin Klein, John D. Baxter, Bo Angelin
Journal: New England Journal of Medicine (2010)

Dyslipidemia increases the risk of atherosclerotic cardiovascular disease and is incompletely reversed by statin therapy alone in many patients. Thyroid hormone lowers levels of serum low-density lipoprotein (LDL) cholesterol and has other potentially favorable actions on lipoprotein metabolism. Consequently, thyromimetic drugs hold promise as lipid-lowering agents if adverse effects can be avoided.We performed a randomized, placebo-controlled, double-blind, multicenter trial to assess the safety and efficacy of the thyromimetic compound eprotirome (KB2115) in lowering the level of serum LDL cholesterol in patients with hypercholesterolemia who were already receiving simvastatin or atorvastatin. In addition to statin treatment, patients received either eprotirome (at a dose of 25, 50, or 100 microg per day) or placebo. Secondary outcomes were changes in levels of serum apolipoprotein B, triglycerides, and Lp(a) lipoprotein. Patients were monitored for potential adverse thyromimetic effects on the heart, bone, and pituitary.The addition of placebo or eprotirome at a dose of 25, 50, or 100 microg daily to statin treatment for 12 weeks reduced the mean level of serum LDL cholesterol from 141 mg per deciliter (3.6 mmol per liter) to 127, 113, 99, and 94 mg per deciliter (3.3, 2.9, 2.6, and 2.4 mmol per liter), respectively, (mean reduction from baseline, 7%, 22%, 28%, and 32%). Similar reductions were seen in levels of serum apolipoprotein B, triglycerides, and Lp(a) lipoprotein. Eprotirome therapy was not associated with adverse effects on the heart or bone. No change in levels of serum thyrotropin or triiodothyronine was detected, although the thyroxine level decreased in patients receiving eprotirome.In this 12-week trial, the thyroid hormone analogue eprotirome was associated with decreases in levels of atherogenic lipoproteins in patients receiving treatment with statins. (ClinicalTrials.gov number, NCT00593047.)
Cardiovascular risk reduction in hypertensive black patients with left ventricular hypertrophy
Authors: Stevo Julius, Michael H Alderman, Gareth Beevers, Björn Dahlöf, Richard B Devereux, Janice G Douglas, Jonathan M Edelman, Katherine E Harris, Sverre E Kjeldsen, Shawna Nesbitt, Otelio S Randall, Jackson T Wright
Journal: Journal of the American College of Cardiology (2004)
Fatigue in non-alcoholic fatty liver disease (NAFLD) is significant and associates with inactivity and excessive daytime sleepiness but not with liver disease severity or insulin resistance
Authors: J L Newton, D E J Jones, E Henderson, L Kane, K Wilton, A D Burt, C P Day
Journal: Gut (2008)

To quantify fatigue in non-alcoholic fatty liver disease (NAFLD), to determine whether perceived fatigue reflects impairment of physical function and to explore potential causes.A cohort study was carried out on 156 consecutive patients with histologically proven NAFLD studied in two cohorts. Phase 1 determined the perceived fatigue experienced by NAFLD patients (assessed using the Fatigue Impact Scale (FIS)) in comparison with normal and liver disease controls, and the relationship to physical function (actigraphy). In phase 2, biological associations of fatigue in NAFLD were explored.Fatigue was markedly higher in NAFLD patients than in controls (mean (SD) FIS 51 (38) vs 8 (12), p<0.001). NAFLD patients showed significantly lower physical activity over 6 days (7089 (2909) mean steps/day vs 8676 (2894), p = 0.02). A significant inverse correlation was seen between FIS and physical activity (r = 0.1, p = 0.02). Fatigue experienced by NAFLD patients was similar to that in primary biliary cirrhosis (n = 36) (FIS 64 (9) vs 61 (2), p = NS). No association was seen between FIS and biochemical and histological markers of liver disease severity or insulin resistance (homeostasis model assessment (HOMA)) (r < 0.005). Significant association was seen between fatigue severity and daytime somnolence (Epworth Sleepiness Scale) (r = 0.2, p < 0.001).Fatigue is a significant problem in NAFLD, is similar in degree to that in primary biliary cirrhosis patients and is associated with impairment in physical function. Fatigue in NAFLD appears to be unrelated to either severity of underlying liver disease or insulin resistance, but is associated with significant daytime somnolence.
Withdrawal from paroxetine can be severe, warns FDA
Authors: A. Tonks
Journal: BMJ (2002)

GlaxoSmithKline, a leading drugs manufacturer, was last week forced to admit that paroxetine, a widely prescribed antidepressant and the company's best selling drug, can cause severe withdrawal symptoms when stopped.

The Food and Drug Administration in the United States published a new product warning about the drug, and in the same week the International Federation of Pharmaceutical Manufacturers Associations declared the company guilty of misleading the public about paroxetine on US television a year ago.

“This drug has been promoted for years as safe and easy to discontinue,” said Charles Medawar, head of Social Audit, a consumer …
HNF1β Is Essential for Nephron Segmentation during Nephrogenesis
Authors: Richard W. Naylor, Aneta Przepiorski, Qun Ren, Jing Yu, Alan J. Davidson
Journal: Journal of the American Society of Nephrology (2012)

Nephrons comprise a blood filter and an epithelial tubule that is subdivided into proximal and distal segments, but what directs this patterning during kidney organogenesis is not well understood. Using zebrafish, we found that the HNF1β paralogues hnf1ba and hnf1bb, which encode homeodomain transcription factors, are essential for normal segmentation of nephrons. Embryos deficient in hnf1ba and hnf1bb did not express proximal and distal segment markers, yet still developed an epithelial tubule. Initiating hnf1ba/b expression required Pax2a and Pax8, but hnf1ba/b-deficient embryos did not exhibit the expected downregulation of pax2a and pax8 at later stages of development, suggesting complex regulatory loops involving these molecules. Embryos deficient in hnf1ba/b also did not express the irx3b transcription factor, which is responsible for differentiation of the first distal tubule segment. Reciprocally, embryos deficient in irx3b exhibited downregulation of hnf1ba/b transcripts in the distal early segment, suggesting a segment-specific regulatory circuit. Deficiency of hnf1ba/b also led to ectopic expansion of podocytes into the proximal tubule domain. Epistasis experiments showed that the formation of podocytes required wt1a, which encodes the Wilms' tumor suppressor-1 transcription factor, and rbpj, which encodes a mediator of canonical Notch signaling, downstream or parallel to hnf1ba/b. Taken together, these results suggest that Hnf1β factors are essential for normal segmentation of nephrons during kidney organogenesis.
Management of Hyperglycemia in the Hospital Setting
Authors: Silvio E. Inzucchi
Journal: New England Journal of Medicine (2006)

A 53-year-old woman with asthma and multilobar pneumonia is admitted with respiratory failure. She is intubated and treated with antibiotics, albuterol, and methylprednisolone. A random blood glucose measurement obtained on admission shows a level of 183 mg per deciliter (10.2 mmol per liter). After 3 hours in the intensive care unit, she has a capillary glucose level of 264 mg per deciliter (14.7 mmol per liter). She has no history of diabetes. Should her hyperglycemia be treated, and if so, how?
Critical Appraisal of Clinical Practice Guidelines for Adaptation in the Evidence-Based Guideline “Prevention of Skin Cancer”
Authors: Sonia Petrarca, Markus Follmann, Eckhard W. Breitbart, Sandra Nolte
Journal: JAMA Dermatology (2013)

<h3>Importance</h3>During guideline development, it is essential to systematically review existing guidelines that may be suitable for adaptation; however, such review is laborious and may not always uncover useful guidelines.<h3>Objective</h3>To identify existing clinical practice guidelines and assess their methodologic quality and suitability for adaptation in the German evidence-based guideline “Prevention of Skin Cancer.”<h3>Evidence Acquisition</h3>A systematic literature search was performed across a range of databases and homepages of guideline development institutions. The AGREE Instrument (Appraisal of Guidelines Research and Evaluation) was used to assess the methodologic quality of selected guidelines.<h3>Results</h3>A total of 480 citations were identified and screened. Of these, 12 guidelines were deemed suitable for potential adaptation. After comprehensive quality assessment, only 2 melanoma guidelines, one from Australia/New Zealand and the other from Scotland, were identified as being of high methodologic quality according to predefined selection criteria. Subsequent synopsis, however, revealed that neither of these guidelines was sufficiently comprehensive for full adaptation.<h3>Conclusions and Relevance</h3>It is surprising that most existing skin cancer guidelines that contain aspects on prevention are not appropriate for adaptation, with most lacking methodologic quality, particularly rigor applied during the development process. Of the 2 guidelines that met the predefined quality criteria, only a few aspects—limited to malignant melanoma—were adaptable. We conclude that, despite the labor-intensive search for existing guidelines, a de novo development, including systematic literature review, is indispensible for the development of the German evidence-based guideline Prevention of Skin Cancer.
The Denver Developmental Screening Test
Authors: Nancy L. Brightwell
Journal: JAMA (1973)

<h3>To the Editor.—</h3> It has recently been suggested that the use of the raisin in the Denver Developmental Screening Test (DDST) is not adequate to determine whether or not a child has normal vision (223:921, 1973). However, the raisin in the DDST is not intended as a test of vision, and the fact that only very poor vision is needed to locate the raisin serves to increase the value of the test for its intended use. The four tests in which only the raisin is used ("regards raisin," "rakes raisin, attains," "thumb-finger grasp," and "neat pincer grasp of raisin") are designed to evaluate fine motor skills. Because the raisin can be seen so easily, a failure in any of these areas cannot be attributed to poor eyesight. The value of any test, such as the DDST, depends upon its proper utilization. The DDST Manual clearly describes the proper performance of
Both Tadalafil and Dexamethasone May Reduce the Incidence of High-Altitude Pulmonary Edema
Authors: Marco Maggiorini, Hans-Peter Brunner-La Rocca, Simon Peth, Manuel Fischler, Thomas Böhm, Alain Bernheim, Stefanie Kiencke, Konrad E. Bloch, Christoph Dehnert, Robert Naeije, Thomas Lehmann, Peter Bärtsch, Heimo Mairbäurl
Journal: Annals of Internal Medicine (2006)

Background: High-altitude pulmonary edema (HAPE) is caused by exaggerated hypoxic pulmonary vasoconstriction associated with decreased bioavailability of nitric oxide in the lungs and by impaired reabsorption of alveolar fluid. Objective: To investigate whether dexamethasone or tadalafil reduces the incidence of HAPE and acute mountain sickness (AMS) in adults with a history of HAPE. Design: Randomized, double-blind, placebo-controlled study performed in summer 2003. Setting: Ascent from 490 m within 24 hours and stay for 2 nights at 4559 m. Patients: 29 adults with previous HAPE. Intervention: Prophylactic tadalafil (10 mg), dexamethasone (8 mg), or placebo twice daily during ascent and stay at 4559 m. Measurements: Chest radiography was used to diagnose HAPE. A Lake Louise score greater than 4 defined AMS. Systolic pulmonary artery pressure was measured by using Doppler echocardiography, and nasal potentials were measured as a surrogate marker of alveolar sodium transport. Results: Two participants who received tadalafil developed severe AMS on arrival at 4559 m and withdrew from the study; they did not have HAPE at that time. High-altitude pulmonary edema developed in 7 of 9 participants receiving placebo and 1 of the remaining 8 participants receiving tadalafil but in none of the 10 participants receiving dexamethasone (P = 0.007 for tadalafil vs. placebo; P < 0.001 for dexamethasone vs. placebo). Eight of 9 participants receiving placebo, 7 of 10 receiving tadalafil, and 3 of 10 receiving dexamethasone had AMS (P = 1.0 for tadalafil vs. placebo; P = 0.020 for dexamethasone vs. placebo). At high altitude, systolic pulmonary artery pressure increased less in participants receiving dexamethasone (16 mm Hg [95% CI, 9 to 23 mm Hg]) and tadalafil (13 mm Hg [CI, 6 to 20 mm Hg]) than in those receiving placebo (28 mm Hg [CI, 20 to 36 mm Hg]) (P = 0.005 for tadalafil vs. placebo; P = 0.012 for dexamethasone vs. placebo). No statistically significant difference between groups was found in change in nasal potentials and expression of leukocyte sodium transport protein messenger RNA. Limitations: The study involved a small sample of adults with a history of HAPE. Conclusions: Both dexamethasone and tadalafil decrease systolic pulmonary artery pressure and may reduce the incidence of HAPE in adults with a history of HAPE. Dexamethasone prophylaxis may also reduce the incidence of AMS in these adults. ClinicalTrials.gov identifier: NCT00274430
Glutamine-based PET imaging facilitates enhanced metabolic evaluation of gliomas in vivo
Authors: Sriram Venneti, Mark P. Dunphy, Hanwen Zhang, Kenneth L. Pitter, Patrick Zanzonico, Carl Campos, Sean D. Carlin, Gaspare La Rocca, Serge Lyashchenko, Karl Ploessl, Daniel Rohle, Antonio M. Omuro, Justin R. Cross, Cameron W. Brennan, Wolfgang A. Weber, Eric C. Holland, Ingo K. Mellinghoff, Hank F. Kung, Jason S. Lewis, Craig B. Thompson
Journal: Science Translational Medicine (2015)

Glutamine-based PET imaging takes advantage of gliomas’ glutamine addiction and can be used to assess metabolic nutrient uptake in gliomas.
MORAL AND POLICY ISSUES IN LONG-ACTING CONTRACEPTION
Authors: George F. Brown, Ellen H. Moskowitz
Journal: Annual Review of Public Health (1997)

The advent of reversible long-acting contraceptives-IUDs, injectables and implants-has provided women throughout the world with valuable new fertility regulation options. These highly effective methods, together with male and female sterilization, have proven to be enormously popular and are now used by the majority of women and men who are currently contracepting worldwide. Despite their remarkable popularity, long-acting contraceptives have engendered considerable controversy. Political, ethical, and safety questions have emerged, stemming from the ways in which these contraceptives have been developed and used over the course of this century. At the heart of the concern is the issue of reproductive rights and freedom. This paper reviews the history of the development of long-acting contraceptives, including the prospect of new methods that will likely emerge from ongoing research and development. It also examines the history, in the United States and in developing countries, of the use and abuse of long-acting methods, including sterilization, in the context of eugenics and population control policies. It then describes a new paradigm of reproductive health and rights that has emerged from the International Conference on Population Development in Cairo, and which offers an enlightened approach to future policies and programs. In light of the wide variety of ways in which long-acting contraceptives have been provided, the paper examines the rights and responsibilities of governments, family planning providers, and individuals. An ethical framework for the use of long-acting methods is discussed, and public policies for the future are proposed.
Abstract 3784: AME-133v, a humanized, Fc-engineered anti-CD20 monoclonal antibody, demonstrates greater B cell depletion than Rituxan <i>in vitro</i>
Authors: Jennifer L. Wayne, Mary-Ann Campbell, Shashi Marulappa, Vinay Jain
Journal: Cancer Research (2012)

Abstract Purpose The efficacy of AME-133v in depleting B lymphocytes was compared in vitro to that of Rituxan, and the effect of FcαRIII genotype was assessed. Methods Blood samples from 37 healthy donors were collected and genotyped for FcαRIII polymorphism. Varying concentrations of AME-133v or Rituxan were applied to samples and CD19+ peripheral circulating B lymphocytes were measured using fluorescence-activated cell sorting (FACS). B cell depletion was listed as a percentage of baseline level. Results In an in vitro whole blood assay, AME-133v was more effective in depleting B lymphocytes from baseline levels than Rituxan, particularly at increasing concentrations (Table 1). Significant differences were found between treatments averaged over doses, between doses averaged over treatments, and between treatments depending on dose, all with p&amp;lt;0.0001. AME-133v's superior effect in depleting B cells is independent of dose (p&amp;lt;0.001), but caused greater B cell depletion at lower concentrations of antibody. In both AME-133v and Rituxan treatments, VF and FF patients demonstrated less B cell depletion, corroborating previous data citing decreased response to Rituxan among F-carriers and indicating improved pharmacodynamics of AME-133v. Conclusion AME-133v is engineered for a 6-fold more potent effector function in antibody-dependent cell-mediated cytotoxicity (ADCC) compared to Rituxan, which is elucidated through improved B cell depletion, across doses. Depletion in AME-133v-treated patients was also greater across all genotypes, suggesting superior pharmacodynamics of AME-133v in the low-responding F-carrier population. These findings indicate relevant biological activity of the antibody and suggest that AME-133v may provide additional clinical benefit for low-affinity FcαRIII patients. A randomized trial is being planned to compare clinical efficacy of AME-133v vs. Rituxan, targeting low-affinity FcαRIII patients. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3784. doi:1538-7445.AM2012-3784