tbuckley/cabot-search huggingface dataset:
Response to Single and Divided Doses of Shiga Toxin-1 in a Primate Model of Hemolytic Uremic Syndrome
Authors: RICHARD L. SIEGLER, THEODORE J. PYSHER, VERNON L. TESH, FLETCHER B. TAYLOR
Journal: Journal of the American Society of Nephrology (2001)

Abstract. Postdiarrheal hemolytic uremic syndrome is caused by Shiga toxin (Stx)-producing Escherichia coli . It was shown previously that the baboon, like the human, has glycolipid receptors for Stx in the gut and the kidney and that a single 50- to 200-ng/kg intravenous dose of purified Stx-1 results in thrombocytopenia, hemolytic anemia, and renal thrombotic microangiopathy. For further characterization of factors that modulate disease expression, the baboon's response to the intravenous administration of 100 ng/kg Stx-1 given either rapidly as a single bolus or slowly as four 25-ng/kg doses at 12-h intervals was compared. Animals that received the Stx-1 as a single dose developed thrombocytopenia, schistocytosis, and acute renal failure. Urinary but not plasma tumor necrosis factor-α concentrations rose significantly by 6 h and then declined rapidly. Urinary and plasma interleukin-6 concentrations rose later. Glomeruli showed reduced patency of capillary loops, fragmented red blood cells, fibrin and platelet microthrombi, necrosis and detachment of endothelial cells, and accumulation of flocculent material in subendothelial spaces. Damage to tubular epithelium and peritubular capillary endothelium also was seen. Animals that received four divided doses of Stx-1 developed no clinical or histologic features of hemolytic uremic syndrome. It is concluded that in the primate model, disease expression is modulated by the rate of Stx administration, and it is speculated that in the human, the rate of Stx absorption from the gut is one determinant of disease severity.
Role for Sterol Regulatory Element-Binding Protein in Activation of Endothelial Cells by Phospholipid Oxidation Products
Authors: Michael Yeh, Amy L. Cole, Jenny Choi, Yi Liu, Dmitry Tulchinsky, Jian-Hua Qiao, Michael C. Fishbein, Alek N. Dooley, Talin Hovnanian, Kevin Mouilleseaux, Devendra K. Vora, Wen-Pin Yang, Peter Gargalovic, Todd Kirchgessner, John Y.-J. Shyy, Judith A. Berliner
Journal: Circulation Research (2004)

Oxidized phospholipids, including oxidation products of palmitoyl-arachidonyl-phosphatidyl choline (PAPC), are mediators of inflammation in endothelial cells (ECs) and known to induce several chemokines, including interleukin-8 (IL-8). In this study, we show that oxidized PAPC (OxPAPC), which accumulates in atherosclerotic lesions, paradoxically depletes endothelial cholesterol, causing caveolin-1 internalization from the plasma membrane to the endoplasmic reticulum and Golgi, and activates sterol regulatory element-binding protein (SREBP). Cholesterol loading reversed these effects. SREBP activation resulted in increased transcription of the low-density lipoprotein receptor, a target gene of SREBP. We also provide evidence that cholesterol depletion and SREBP activation are signals for OxPAPC induction of IL-8. Cholesterol depletion by methyl-beta-cyclodextrin induced IL-8 synthesis in a dose-dependent manner. Furthermore, cholesterol loading of ECs by either the cholesterol-cyclodextrin complex or caveolin-1 overexpression inhibited OxPAPC induction of IL-8. These observations suggest that changes in cholesterol level can modulate IL-8 synthesis in ECs. The OxPAPC induction of IL-8 was mediated through the increased binding of SREBP to the IL-8 promoter region, as revealed by mobility shift assays. Overexpression of either dominant-negative SREBP cleavage-activating protein or 25-hydroxycholesterol significantly suppressed the effect of OxPAPC on IL-8 transcription. A role for SREBP activation in atherosclerosis is suggested by the observation that EC nuclei showed strong SREBP staining in human atherosclerotic lesions. The current studies suggest a novel role for endothelial cholesterol depletion and subsequent SREBP activation in inflammatory processes in which phospholipid oxidation products accumulate.
Efficacy of entecavir in patients with chronic hepatitis B resistant to both lamivudine and adefovir or to lamivudine alone
Authors: Ju Hyun Shim, Dong Jin Suh, Kang Mo Kim, Young-Suk Lim, Han Chu Lee, Young-Hwa Chung, Yung Sang Lee
Journal: Hepatology (2009)

Entecavir (ETV) is currently recommended as a rescue therapy purely for adefovir (ADV)-resistant chronic hepatitis B virus (HBV) infections. We evaluated the efficacy of ETV in patients who were resistant to lamivudine (LAM)/ADV sequential therapy and in those resistant to LAM monotherapy. Fifty LAM/ADV-resistant and 38 LAM-resistant patients who received ETV 1 mg/day for at least 48 weeks were enrolled. Mean baseline serum HBV DNA and alanine aminotransferase (ALT) levels were significantly lower in the LAM/ADV-resistant group, compared with the LAM-resistant group (6.90 versus 7.62 log10 copies/mL and 102.6 versus 160.2 IU/L; both P &lt; 0.05); hepatitis B e antigen (HBeAg) status and LAM-resistant mutation patterns were similar in the two groups. At week 48, mean reductions in HBV DNA and ALT levels were significantly less in the LAM/ADV-resistant group (−2.96 versus −4.86 log10 copies/mL and −68.3 versus −128.9 IU/L; both P &lt; 0.05). Achievement of undetectable HBV DNA was also less common in the LAM/ADV-resistant group (10.0% versus 34.2%; P = 0.006), although the rates of HBeAg loss and ALT normalization did not differ between the two groups. Resistance to both LAM and ADV was an independent risk factor for failure of HBV DNA negativity at week 48 (odds ratio, 0.138; P = 0.019). In both LAM/ADV-resistant and LAM-resistant groups, primary responders (≥1 log decline in HBV DNA at week 12) achieved a significantly greater decrease in HBV DNA levels over the 48-week period, compared with primary nonresponders (−4.18 versus −0.97 and −5.37 versus −2.15 log10 copies/mL, respectively; both P &lt; 0.05). Conclusion: The 48-week ETV treatment was less effective in LAM/ADV-resistant than in LAM-resistant patients. Continuing ETV monotherapy could be determined based on the virological response at 12 weeks in LAM/ADV-resistant patients. (Hepatology 2009.)
Effects of Oral Fructose in Normal, Diabetic, and Impaired Glucose Tolerance Subjects
Authors: Phyllis A Crapo, Orville G Kolterman, Jerrold M Olefsky
Journal: Diabetes Care (1980)

We studied the acute effects of oral ingestion of 50-g loads of dextrose, sucrose, and fructose on postprandial serum glucose, insulin, and plasma glucagon responses in 9 normal subjects, 10 subjects with impaired glucose tolerance, and 17 non-insulin-dependent diabetic subjects. The response to each carbohydrate was quantified when the respective carbohydrate was given alone in a drink or when given in combination with protein and fat in a test meal. The data demonstrate that (1) fructose ingestion resulted in significantly lower serum glucose and insulin responses than did sucrose or dextrose ingestion in all study groups, either when given alone or in the test meal; (2) although fructose ingestion always led to the least glycemic response compared with the other hexoses, the serum glucose response to fructose was increased the more glucose intolerant the subject; (3) urinary glucose excretion during the 3 h after carbohydrate ingestion was greatest after dextrose and least after fructose in all groups. In conclusion, fructose ingestion results in markedly lower serum glucose and insulin responses and less glycosuria than either dextrose or sucrose, both when given alone or as a constituent in a test meal. However, as glucose tolerance worsens, an increasingly greater glycemic response to fructose is seen.
Cardiomyopathies in disorders of oxidative metabolism
Authors: C Antozzi
Journal: Cardiovascular Research (1997)

Primary cardiomyopathy is an important cause of mortality in children and adults. Apart from inherited disorders of myocardial contractile and structural proteins, several defects of energy metabolism may cause cardiomyopathy. Most of the energy required for myocardial contraction is derived from aerobic metabolism. Faulty aerobic metabolism involving the heart may be due to defects of mitochondrial oxidative phosphorylation or to defects of fatty acid oxidation. Considerable advances have been made in the last 10 years in understanding the biochemical and molecular characteristics of mitochondrial disorders. Several point mutations or large-scale re-arrangements of mitochondrial DNA have been identified in patients with cardiomyopathy, either as part of complex multisystem syndromes or as the main clinical feature. Inborn errors of fatty acid oxidation are reported with increasing frequency as a cause of metabolic dysfunction, myopathy, cardiomyopathy, and sudden death in childhood. Advances in biochemical and molecular genetic techniques have considerably improved our understanding of the metabolic disorders causing cardiomyopathy, providing new tools for classification and diagnosis of candidate patients. The present review focuses on defects of mitochondrial oxidative metabolism associated with cardiomyopathy.
Mimicry of a Cellular Low Energy Status Blocks Tumor Cell Anabolism and Suppresses the Malignant Phenotype
Authors: Johannes V. Swinnen, Annelies Beckers, Koen Brusselmans, Sophie Organe, Joanna Segers, Leen Timmermans, Frank Vanderhoydonc, Ludo Deboel, Rita Derua, Etienne Waelkens, Ellen De Schrijver, Tine Van de Sande, Agnès Noël, Fabienne Foufelle, Guido Verhoeven
Journal: Cancer Research (2005)

Abstract Aggressive cancer cells typically show a high rate of energy-consuming anabolic processes driving the synthesis of lipids, proteins, and DNA. Here, we took advantage of the ability of the cell-permeable nucleoside 5-aminoimidazole-4-carboxamide (AICA) riboside to increase the intracellular levels of AICA ribotide, an AMP analogue, mimicking a low energy status of the cell. Treatment of cancer cells with AICA riboside impeded lipogenesis, decreased protein translation, and blocked DNA synthesis. Cells treated with AICA riboside stopped proliferating and lost their invasive properties and their ability to form colonies. When administered in vivo, AICA riboside attenuated the growth of MDA-MB-231 tumors in nude mice. These findings point toward a central tie between energy, anabolism, and cancer and suggest that the cellular energy sensing machinery in cancer cells is an exploitable target for cancer prevention and/or therapy.
Anticancer Activity of CX-3543: A Direct Inhibitor of rRNA Biogenesis
Authors: Denis Drygin, Adam Siddiqui-Jain, Sean O'Brien, Michael Schwaebe, Amy Lin, Josh Bliesath, Caroline B. Ho, Chris Proffitt, Katy Trent, Jeffrey P. Whitten, John K. C. Lim, Daniel Von Hoff, Kenna Anderes, William G. Rice
Journal: Cancer Research (2009)

Hallmark deregulated signaling in cancer cells drives excessive ribosome biogenesis within the nucleolus, which elicits unbridled cell growth and proliferation. The rate-limiting step of ribosome biogenesis is synthesis of rRNA (building blocks of ribosomes) by RNA Polymerase I (Pol I). Numerous kinase pathways and products of proto-oncogenes can up-regulate Pol I, whereas tumor suppressor proteins can inhibit rRNA synthesis. In tumorigenesis, activating mutations in certain cancer-associated kinases and loss-of-function mutations in tumor suppressors lead to deregulated signaling that stimulates Pol I transcription with resultant increases in ribosome biogenesis, protein synthesis, cell growth, and proliferation. Certain anticancer therapeutics, such as cisplatin and 5-fluorouracil, reportedly exert, at least partially, their activity through disruption of ribosome biogenesis, yet many prime targets for anticancer drugs within the ribosome synthetic machinery of the nucleolus remain largely unexploited. Herein, we describe CX-3543, a small molecule nucleolus-targeting agent that selectively disrupts nucleolin/rDNA G-quadruplex complexes in the nucleolus, thereby inhibiting Pol I transcription and inducing apoptosis in cancer cells. CX-3543 is the first G-quadruplex interactive agent to enter human clinical trials, and it is currently under evaluation against carcinoid/neuroendocrine tumors in a phase II clinical trial.
Electron and light microscopical observations and serological findings in rheumatoid arthritis.
Authors: A E Helder, T M Feltkamp-Vroom, R L Nienhuis
Journal: Annals of the Rheumatic Diseases (1973)

From this work suggestions arose concerning a possible aetiological agent in rheumatoid arthritis.It has been demonstrated that aggregates of tubular structures (TS), morphologically resembling uncapsulated nucleocapsids of paramyxoviruses may be present in the cytoplasm of endothelial cells of blood vessels occurring in rheumatoid synovial tissue (Gyorkey, Min, and Gyorkey, 1969a).The presence of nuclear bodies and virus-like particles in the cells of the rheumatoid synovial membrane (Neumark and Farkas, 1970; Neumark, Hollos, and Farkas, 1971) is also suggestive of a virus involvement.The possible role of bacterial (Svartz, 1972) or mycoplasma infection (Jansson, Makisara, Vainio, Sneliman, and Tuuri, 1971a; Jansson, Maikisara, Vainio, Vainio, Snellman, and Tuuri, 1971b; Williams, Brostoff, and Roitt, 1970) in the development of rheumatoid arthritis has also been suggested.The purpose of this paper is to present the electron and light micros- copical observations in tissues of patients with rheumatoid arthritis as well as the serological findings and to discuss our data in comparison with those described by other investigators.
Relationship between Levels of Indinavir in Hair and Virologic Response to Highly Active Antiretroviral Therapy
Authors: Louis Bernard, Albert Vuagnat, Gilles Peytavin, Marie-Charlotte Hallouin, Damien Bouhour, Thu Huyen Nguyen, Jean Louis Vildé, François Bricaire, Gilles Raguin, Pierre de Truchis, David Ghez, Michel Duong, Christian Perronne
Journal: Annals of Internal Medicine (2002)

Suboptimal levels of antiretroviral drugs result in virologic failure in HIV-infected patients treated with highly active antiretroviral therapy (HAART).To assess the relationship between levels of indinavir in hair and virologic outcome.Cross-sectional study.7 AIDS clinics in France.89 HIV-infected patients who received HAART that included indinavir.Patients were classified as responders or nonresponders on the basis of viremia at the time of hair collection. In nonresponders, levels of indinavir in hair and resistance mutations in the protease gene were assessed at baseline and at the time of indinavir measurement.Mean indinavir levels (+/-SD) were significantly higher in the 65 responders than in the 24 nonresponders (24.4 +/- 16 microg/g vs. 12.9 +/- 8.6 microg/g) (P < 0.001). Nonresponders with intermediate levels of indinavir in hair had more mutations in the protease gene than did nonresponders with low levels of indinavir in hair.Indinavir levels in hair are associated with virologic outcome in patients receiving HAART.
TCT-168 Short Term follow up of Percutaneuos Closure Of Perimembranous Ventricular Septal Defects Using The Second Generation Amplatzer Occluders
Authors: Makram R. Ebeid, Sarosh Batlivala, Ahmad Charaf Eddine, Avichal Aggarwal, Jorge Salazar, Mary Taylor
Journal: Journal of the American College of Cardiology (2014)
Physicians and Strikes: Can a Walkout Over the Malpractice Crisis Be Ethically Justified?
Authors: Autumn Fiester
Journal: The American Journal of Bioethics (2004)

Malpractice insurance rates have created a crisis in American medicine. Rates are rising and reimbursements are not keeping pace. In response, physicians in the states hardest hit by this crisis are feeling compelled to take political action, and the current action of choice seems to be physician strikes. While the malpractice insurance crisis is acknowledged to be severe, does it justify the extreme action of a physician walkout? Should physicians engage in this type of collective action, and what are the costs to patients and the profession when such action is taken? I will offer three related arguments against physician strikes that constitute a prima facie prohibition against such action: first, strikes are intended to cause harm to patients; second, strikes are an affront to the physician-patient relationship; and, third, strikes risk decreasing the public's respect for the medical profession. As with any prima facie obligation, there are justifying conditions that may override the moral prohibition, but I will argue that the current malpractice crisis does not rise to the level of such a justifying condition. While the malpractice crisis demands and justifies a political response on the part of the nation's physicians, strikes and slow-downs are not an ethically justified means to the legitimate end of controlling insurance costs.
Achievement of at Least Very Good Partial Response Is a Simple and Robust Prognostic Factor in Patients With Multiple Myeloma Treated With High-Dose Therapy: Long-Term Analysis of the IFM 99-02 and 99-04 Trials
Authors: Jean-Luc Harousseau, Herve Avet-Loiseau, Michel Attal, Catherine Charbonnel, Frederic Garban, Cyrille Hulin, Mauricette Michallet, Thierry Facon, Laurent Garderet, Gerald Marit, Nicolas Ketterer, Thierry Lamy, Laurent Voillat, Francois Guilhot, Chantal Doyen, Claire Mathiot, Philippe Moreau
Journal: Journal of Clinical Oncology (2009)

The prognostic impact of complete response (CR) achievement in multiple myeloma (MM) has been shown mostly in the context of autologous stem-cell transplantation. Other levels of response have been defined because, even with high-dose therapy, CR is a relatively rare event. The purpose of this study was to analyze the prognostic impact of very good partial response (VGPR) in patients treated with high-dose therapy.All patients were included in the Intergroupe Francophone du Myelome 99-02 and 99-04 trials and treated with vincristine, doxorubicin, and dexamethasone (VAD) induction therapy followed by double autologous stem-cell transplantation (ASCT). Best post-ASCT response assessment was available for 802 patients.With a median follow-up of 67 months, median event-free survival (EFS) and 5-year EFS were 42 months and 34%, respectively, for 405 patients who achieved at least VGPR after ASCT versus 32 months and 26% in 288 patients who achieved only partial remission (P = .005). Five-year overall survival (OS) was significantly superior in patients achieving at least VGPR (74% v 61% P = .0017). In multivariate analysis, achievement of less than VGPR was an independent factor predicting shorter EFS and OS. Response to VAD had no impact on EFS and OS. The impact of VGPR achievement on EFS and OS was significant in patients with International Staging System stages 2 to 3 and for patients with poor-risk cytogenetics t(4;14) or del(17p).In the context of ASCT, achievement of at least VGPR is a simple prognostic factor that has importance in intermediate and high-risk MM and can be informative in more patients than CR.
Interventions to Enhance Patient Adherence to Medication Prescriptions
Authors: Heather P McDonald, Amit X Garg, R Brian Haynes
Journal: JAMA (2002)

ContextLow adherence with prescribed treatments is ubiquitous and undermines treatment benefits.ObjectiveTo systematically review published randomized controlled trials (RCTs) of interventions to assist patients' adherence to prescribed medications.Data SourcesA search of MEDLINE, CINAHL, PSYCHLIT, SOCIOFILE, IPA, EMBASE, The Cochrane Library databases, and bibliographies was performed for records from 1967 through August 2001 to identify relevant articles of all RCTs of interventions intended to improve adherence to self-administered medications.Study Selection and Data ExtractionStudies were included if they reported an unconfounded RCT of an intervention to improve adherence with prescribed medications for a medical or psychiatric disorder; both adherence and treatment outcome were measured; follow-up of at least 80% of each study group was reported; and the duration of follow-up for studies with positive initial findings was at least 6 months. Information on study design features, interventions, controls, and findings (adherence rates and patient outcomes) were extracted for each article.Data SynthesisStudies were too disparate to warrant meta-analysis. Forty-nine percent of the interventions tested (19 of 39 in 33 studies) were associated with statistically significant increases in medication adherence and only 17 reported statistically significant improvements in treatment outcomes. Almost all the interventions that were effective for long-term care were complex, including combinations of more convenient care, information, counseling, reminders, self-monitoring, reinforcement, family therapy, and other forms of additional supervision or attention. Even the most effective interventions had modest effects.ConclusionsCurrent methods of improving medication adherence for chronic health problems are mostly complex, labor-intensive, and not predictably effective. The full benefits of medications cannot be realized at currently achievable levels of adherence; therefore, more studies of innovative approaches to assist patients to follow prescriptions for medications are needed.
A1C: Recommendations, Debates, and Questions
Authors: Zachary T. Bloomgarden
Journal: Diabetes Care (2009)

A series of elegant investigations some 4 decades ago led to the realization that elevated levels of certain hemoglobin components are found in individuals with diabetes (1).The useful measurement of A1C became standard in assessment of glycemia (2).A1C, rather than direct measures of glycemia, is now used as the "goal" for diabetes treatment (3,4). Should A1C be used for diabetes diagnosis?At the 69th Scientific Sessions of the American Diabetes Association (ADA), David Nathan (Boston, MA) discussed the role of A1C in the diagnosis of diabetes in nonpregnant subjects and explained the position advocated by an expert committee of ADA and the European Association for the Study of Diabetes (EASD) that the diagnosis of diabetes may be conveniently based on A1C Ն6.5%, without the need to measure a plasma glucose concentration (5).All methods previously used for the diagnosis of diabetes, he noted, have relied on measuring blood glucose, whether in the fasting state or after a stress, as in the oral glucose tolerance test.He asserted that early attempts to establish the diagnosis of diabetes were hampered by absence of standardization, for example, with different times for blood determination or with different oral glucose loads.Type 1 diabetes usually has characteristic presentation and thus is easily diagnosed, but Nathan observed that type 2 diabetes can be subtle in its onset; analyses of fasting and 2-h postload glucose levels in Korea, Nauru, Egypt, and Taiwan showed unimodal glucose distributions (6), although this may be an artifact of the relative infrequency of dia-
Early-onset lymphoproliferation and autoimmunity caused by germline STAT3 gain-of-function mutations
Authors: Joshua D. Milner, Tiphanie P. Vogel, Lisa Forbes, Chi A. Ma, Asbjørg Stray-Pedersen, Julie E. Niemela, Jonathan J. Lyons, Karin R. Engelhardt, Yu Zhang, Nermina Topcagic, Elisha D. O. Roberson, Helen Matthews, James W. Verbsky, Trivikram Dasu, Alexander Vargas-Hernandez, Nidhy Varghese, Kenneth L. McClain, Lina B. Karam, Karen Nahmod, George Makedonas, Emily M. Mace, Hanne S. Sorte, Gøri Perminow, V. Koneti Rao, Michael P. O’Connell, Susan Price, Helen C. Su, Morgan Butrick, Joshua McElwee, Jason D. Hughes, Joseph Willet, David Swan, Yaobo Xu, Mauro Santibanez-Koref, Voytek Slowik, Darrell L. Dinwiddie, Christina E. Ciaccio, Carol J. Saunders, Seth Septer, Stephen F. Kingsmore, Andrew J. White, Andrew J. Cant, Sophie Hambleton, Megan A. Cooper
Journal: Blood (2014)
Common genetic variation in the HLA region is associated with late-onset sporadic Parkinson's disease
Authors: Taye H Hamza, Cyrus P Zabetian, Albert Tenesa, Alain Laederach, Jennifer Montimurro, Dora Yearout, Denise M Kay, Kimberly F Doheny, Justin Paschall, Elizabeth Pugh, Victoria I Kusel, Randall Collura, John Roberts, Alida Griffith, Ali Samii, William K Scott, John Nutt, Stewart A Factor, Haydeh Payami
Journal: Nature Genetics (2010)