tbuckley/cabot-search huggingface dataset:
The COP9 signalosome is a repressor of replicative stress responses and polyploidization in the regenerating liver
Authors: Martina Panattoni, Laura Maiorino, Anna Lukacs, Lorena Zentilin, Davide Mazza, Francesca Sanvito, Giovanni Sitia, Luca G. Guidotti, Ruggero Pardi
Journal: Hepatology (2014)

Aberrant DNA replication induced by deregulated or excessive proliferative stimuli evokes a “replicative stress response” leading to cell cycle restriction and/or apoptosis. This robust fail-safe mechanism is eventually bypassed by transformed cells, due to ill-defined epistatic interactions. The COP9 signalosome (CSN) is an evolutionarily conserved regulator of cullin ring ligases (CRLs), the largest family of ubiquitin ligases in metazoans. Conditional inactivation of the CSN in several tissues leads to activation of S- or G2-phase checkpoints resulting in irreversible cell cycle arrest and cell death. Herein we ablated COPS5, the CSNs catalytic subunit, in the liver, to investigate its role in cell cycle reentry by differentiated hepatocytes. Lack of COPS5 in regenerating livers causes substantial replicative stress, which triggers a CDKN2A -dependent genetic program leading to cell cycle arrest, polyploidy, and apoptosis. These outcomes are phenocopied by acute overexpression of c-Myc in COPS5 null hepatocytes of adult mice. Conclusion : We propose that combined control of proto-oncogene product levels and proteins involved in DNA replication origin licensing may explain the deleterious consequences of CSN inactivation in regenerating livers and provide insight into the pathogenic role of the frequently observed overexpression of the CSN in hepatocellular carcinoma. (Hepatology 2014;59:2331–2343)
Peasant Spreading Manure
Authors: M. Therese Southgate
Journal: JAMA (2003)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Measuring the Speed of Thought
Authors: Rebecca Voelker
Journal: JAMA (1998)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Haemophilus influenzae serotype B (Hib) seroprevalence in England and Wales in 2009
Authors: S N Ladhani, M E Ramsay, J S Flood, H Campbell, M P Slack, R Pebody, J Findlow, E Newton, M Wilding, R Warrington, H Crawford, S Y Min, K Gray, S Martin, S Frankland, N Bokuvha, G Laher, R Borrow
Journal: Eurosurveillance (2012)

A national seroprevalence study was performed to determine the prevalence of Haemophilus influenzae type b (Hib) antibodies in England and Wales in 2009, when Hib disease incidence was the lowest ever recorded. A total of 2,693 anonymised residual sera from routine diagnostic testing submitted by participating National Health Service hospital laboratories were tested for Hib anti-polyribosyl-ribitol phosphate (PRP) IgG antibodies using a fluorescent bead assay. Median anti-PRP IgG concentrations were highest in toddlers aged 1–4 years (2.65 μg/ml), followed by children aged 5–9 years (1.95 μg/ml). Antibody concentrations were significantly lower after this age, but were still significantly higher among 10–19 year-olds (0.54 μg/ml) compared with adults aged >20 years (0.16 μg/ ml; p<0.0001). Half of the adults (51%) did not have Hib antibody concentrations ≥0.15 μg/ml, the level considered to confer short-term protection. Thus, the current excellent Hib control appears to be the result of high anti-PRP antibody concentrations in children aged up to 10 years, achieved through the various childhood vaccination campaigns offering booster immunisation. The lack of seroprotection in adults emphasises the importance of maintaining control of the disease and, most probably carriage, in children, therefore raising the question as to whether long-term routine boosting of either pre-school children or adolescents may be required.
Ramelteon for Prevention of Delirium in Hospitalized Older Patients
Authors: Stany M. T. Perkisas, Maurits F. J. Vandewoude
Journal: JAMA (2015)

IMPORTANCENo highly effective interventions to prevent delirium have been identified.OBJECTIVE To examine whether ramelteon, a melatonin agonist, is effective for the prevention of delirium. DESIGN, SETTING, AND PARTICIPANTSA multicenter, rater-blinded, randomized placebo-controlled trial was performed in intensive care units and regular acute wards of 4 university hospitals and 1 general hospital.Eligible patients were 65 to 89 years old, newly admitted due to serious medical problems, and able to take medicine orally.Patients were excluded from the study if they had an expected stay or life expectancy of less than 48 hours.INTERVENTIONS Sixty-seven patients were randomly assigned using the sealed envelope method to receive ramelteon (8 mg/d; 33 patients) or placebo (34 patients) every night for 7 days. MAIN OUTCOMES AND MEASURES Incidence of delirium, as defined by the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition).RESULTS Ramelteon was associated with a lower risk of delirium (3% vs 32%; P = .003),with a relative risk of 0.09 (95% CI, 0.01-0.69).Even after risk factors were controlled for, ramelteon was still associated with a lower incidence of delirium (P = .01;odds ratio, 0.07 [95% CI, 0.008-0.54]).The Kaplan-Meier estimates of time to development of delirium were 6.94 (95% CI, 6.82-7.06)days for ramelteon and 5.74 (5.05-6.42)days for placebo.Comparison by log-rank test showed that the frequency of delirium was significantly lower in patients taking ramelteon than in those taking placebo (χ 2 = 9.83; P = .002).CONCLUSIONS AND RELEVANCE Ramelteon administered nightly to elderly patients admitted for acute care may provide protection against delirium.This finding supports a possible pathogenic role of melatonin neurotransmission in delirium.
Abstract 17019: Two Distinct mechanisms by which Na+/Ca2+ dysregulation contributes to Arrhythmogenic Diastolic Ca2+ Release
Authors: Przemyslaw Radwanski, Rengasayee Veeraraghavan, Björn Knollmann, Sándor Györke
Journal: Circulation (2014)

Na + and Ca 2+ imbalance is associated with triggered arrhythmias resulting from diastolic Ca 2+ release (DCR) from sarcoplasmic reticulum (SR). Recent evidence suggests Na + channel blockade to be a promising therapy for pathologies, including catecholaminergic polymorphic ventricular tachycardia (CPVT). However, the specific mechanism(s) as to how Na + /Ca 2+ dysregulation contribute to arrhythmias is unknown. Confocal microscopy of ventricular myocytes isolated from CPVT mice lacking the cardiac calsequestrin was used to assess Ca 2+ handling response to isoproterenol (Iso) and various pharmacological interventions, while electrocardiograms were acquired during catecholamine challenge to assess the roles of various pools of Na + channels in CPVT. We identify two pools of Na + channels: one composed of cardiac-type Na + channels localized to cell periphery, and a ‘ local pool ’ comprised of neuronal Na + channels colocalizing with RyR2 in the T-tubules. Augmenting function of both Na + channel pools with ATX-II in the presence Iso resulted in SR Ca 2+ overload and activation of Ca 2+ /calmodulin-dependent protein kinase II (CaMKII), which precipitated DCR. These, in turn, translated into frequent arrhythmias in CPVT mice. Selectively augmenting function of ‘local pool’ neuronal Na + channels with β-Pompilidotoxin (β-PMTX) precipitated DCR on the cellular level causing frequent arrhythmias during catecholamine challenge in vivo . However, increasing local Na + fluxes reduced SR Ca 2+ load suggesting that local elevation in cytosolic Ca 2+ rather than global SR Ca 2+ overload underlies DCR and arrhythmias under such conditions. These data suggest two distinct mechanisms for Na + /Ca 2+ dysregulation-mediated arrhythmias. The first relies on SR Ca 2+ overload and CaMKII activation and the other on local contribution of Na + -Ca 2+ exchange to DCR. Consideration of these divergent mechanisms may enhance individualized approach to arrhythmia management.
The unfolded-protein-response sensor IRE-1α regulates the function of CD8α+ dendritic cells
Authors: Fabiola Osorio, Simon J Tavernier, Eik Hoffmann, Yvan Saeys, Liesbet Martens, Jessica Vetters, Iris Delrue, Riet De Rycke, Eef Parthoens, Philippe Pouliot, Takao Iwawaki, Sophie Janssens, Bart N Lambrecht
Journal: Nature Immunology (2014)
Formal Discussion of “Cancers of the Pancreas and Biliary Tract: Epidemiological Considerations”
Authors: Edward I. Goldsmith
Journal: Cancer Research (1975)

Summarizing Remarks  The present status of carcinoma of the pancreas is dismal and becoming worse because our treatment is not improving while incidence is increasing. Epidemiological data like those reported by Dr. Fraumeni have highlighted this situation and suggested some new ways to look at the disease.  High-risk groups in the population can be identified, but it is questionable whether screening is feasible with presently available diagnostic methods. If one recently published paper suggesting a tumor-specific protein is correct, it might become reasonable to explore such screening. Although surgical removal of these tumors has become safer and more effective and total pancreatectomy will be used more extensively in coming years, we cannot expect surgery to make an important impact on the disease since 90% of patients are inoperable when first seen.  Since prodromal and/or early malignant changes are not observable in human patients, we should turn vigorously to the creation of an animal model for biliary tract and/or pancreatic tumors. In this regard, existing evidence illustrates the close similarity of baboons to humans in bile chemistry and physiology. Furthermore, pancreatic cancer does occur in animals and suggests that carnivores and/or omnivores might be better candidates than herbivores to serve as animal models. Husbandry, management, and economic consideration make it entirely reasonable to turn to larger animals rather than mega-mice,  if  one is satisfied that phylogenetic similarity to humans and longer life-span are important.  It is reasonable to think that experimental studies following up on these epidemiological clues will produce useful data, and we can then hope that the coming years will produce better progress than we have made in our generation.
Perfectionism and Maladaptive Coping Styles in Patients with Chronic Fatigue Syndrome, Irritable Bowel Syndrome and Fibromyalgia/Arthritis and in Healthy Controls
Authors: Fuschia M. Sirois, Danielle S. Molnar
Journal: Psychotherapy and Psychosomatics (2014)

This is a repository copy of Perfectionism and maladaptive coping styles in patients with chronic fatigue syndrome, irritable bowel syndrome and fibromyalgia/arthritis and in healthy controls..
The Electrical Activity of the Nervous System: A Textbook for Students
Authors: Mary Agnes Burniston Brazier
Journal: JAMA (1952)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
RNA-Based Anti-HIV-1 Gene Therapeutic Constructs in SCID-hu Mouse Model
Authors: Jirong Bai, Nirmal Banda, Nan Sook Lee, John Rossi, Ramesh Akkina
Journal: Molecular Therapy (2002)

Effective suppression of HIV-1 replication requires inhibition of critical viral target molecules. Tat and Rev are indispensable regulatory factors for HIV-1 replication, whereas Env mediates virus entry by direct interaction with surface receptor CD4 and coreceptor CCR5 or CXCR4. Anti-HIV-1 tat-rev and env ribozymes and Rev aptamers were previously demonstrated to provide relatively long-term protection against HIV-1 infection in vitro. However, further improvements in these constructs for clinical application in a stem-cell-based gene therapy setting requires in vivo characterization. Toward this end, we introduced these constructs into CD34+ hematopoietic progenitor cells by retrovirus-mediated gene transduction. Ribozyme- and aptamer-transduced CD34+ cells differentiated normally into multiple lineages of erythroid and myeloid progenies in a colony-forming unit assay. Macrophages that differentiated from the transduced CD34+ cells expressed anti-tat-rev and -env ribozymes and Rev aptamers and displayed their normal characteristic surface markers CD14, CD4, and CCR5. Using the SCID-hu mouse in vivo human thymopoiesis model, we demonstrated that ribozyme- and aptamer-transduced CD34+ cells retained their normal capacity to reconstitute human fetal thymus and liver tissue (thy/liv) grafts. Reconstitution by ribozyme- and aptamer-transduced CD34+ cells reached levels of up to 87% based on HLA surface marker staining. Differentiated thymocytes derived from reconstituted grafts expressed anti-tat-rev and -env ribozymes and Rev aptamers and showed significant resistance to HIV-1 infection upon challenge. Analysis of reconstituted thymocytes by hybridization revealed an average of 0.4 to 2 copies of vector sequences per cell. Southern analysis of proviral integration junctions in progeny thymocytes demonstrated that the human thy/liv grafts were reconstituted by a few primitive hematopoietic stem cells. These results highlight the utility of RNA-based anti-HIV-1 gene therapeutic approaches and their preclinical testing in a surrogate animal model harboring human tissue.
Gastrointestinal and Nutritional Manifestations of the Acquired Immunodeficiency Syndrome
Authors: Donald P. Kotler
Journal: Annals of Internal Medicine (1992)

Part 1 Background: biological and clinical features of HIV infection, Donald P. Kotler introduction to gastrointestinal immunology - host defense immune system in the gut, Hidenori Kawanishi, et al nutrition and immunity, Chitra Prasad and Ranjit Kumar Chandra. Part 2 Clinical manifestations of AIDS: oral complications of HIV infection, Andrew J. Zakarian diagnosis and treatment of gastrointestinal infections in AIDS, E. Rene, et al gastrointestinal neoplasms in AIDS, Milayna Subar, et al hepatobiliary disease in AIDS, Gail M. Comer gross and microscopic pathology of AIDS in the gastrointestinal tract, Frederic Clayton radiologic changes in AIDS, Jeanne Baer and Susan Hilton. Part 3 Nutritional aspects of AIDS: mechanisms of wasting in infection and cancer - an approach to cachexia in AIDS, Carl Grunfeld studies of nutritional status in patients with AIDS, Donald P. Kotler, et al AIDS - enteral and parenteral nutrition support, Steven B. Heymisfield, et al practical dietary recommendations in HIV infection, Cade Fields Newman. Part 4 Other considerations: psychosocial aspects pertaining to nutrition, Kristin E. Weaver establishing a gastrointestinal unit, Sharon Gallagher and William P. Winkler.
Long term effects of advice to reduce dietary salt
Authors: G. A MacGregor
Journal: BMJ (2003)

Editor—That small reductions in salt intake (2 g/day) have a small but significant effect on blood pressure is hardly surprising.1 Nevertheless, in populations this would have a large effect on reducing strokes, heart attacks, and heart failure.


Hooper et al do not ask why reducing salt intake in the long term is so difficult. They claim that the interventions used were intensive, but most studies gave no details about what advice was offered. Furthermore, 75% of salt intake comes from processed food.2 This needs to be avoided or contain less salt. None of the studies provided reduced salt foods. 




Interpreting the study by Hooper et al is not helped by the editor writing the front cover of the BMJ, who seems to have read a different paper and misinterpreted the important positive findings. The confusion is increased by the authors' press release,3 which rightly blames the difficulty in reducing salt intake squarely on the food industry.

This confusion is compounded by errors in the meta-analysis. For example, the 18 month TOPH trial (phase I) was included as an intervention trial over “60 months,” but salt intake was reduced for only 18 months, after which all participants returned to their normal diet. References were misquoted, and the correspondence following these papers was ignored. The totality of evidence for reducing salt is stronger than for any other non-pharmacological treatment.

Ninety five per cent of the population are at risk of developing cardiovascular disease,4 and 40% die from it. There are no controlled trials showing a reduction in mortality on stopping smoking, reducing fat intake alone (without fish oil supplements), reducing salt intake, losing weight, increasing fruit and vegetable consumption, or increasing exercise. For most of these factors no attempt has been made to conduct long term trials, owing to the innate difficulty of conducting and funding such trials and, now, the ethics of randomly putting a group of people on a high salt diet for the rest of their lives. The question that Hooper et al need to consider is what strength of evidence is needed to give dietary and lifestyle advice to try to prevent cardiovascular disease.

The study indicates the importance of reducing salt intake in the population, even by small amounts, particularly in treating high blood pressure.5 The BMJ should publish a retraction of its misleading front cover and read the authors' press release.
Abstract 11584: Left Atrial Appendage Occlusion for Prevention of Stroke in Non-Valvular Atrial Fibrillation: A Meta-Analysis
Authors: Weeranun D Bode, Nikhil Patel, Anil K Gehi
Journal: Circulation (2014)

Introduction: Atrial fibrillation (AF) increases the risk of thromboembolic stroke. When anticoagulation for stroke prevention is contraindicated, left atrial appendage occlusion (LAAO) may be performed. Studies of LAAO have been limited by their small size, disparate patient populations, and lack of control group. To better understand the value of LAAO for prevention of stroke and systemic embolism, we performed a meta-analysis of studies evaluating the efficacy and safety of LAAO in non-valvular AF. Methods: A meta-analysis was performed of the safety and efficacy of LAAO in comparison with standard therapy for stroke prevention in non-valvular AF using random-effects modeling. Because only one trial had a control group comparing the efficacy of LAAO to standard therapy (warfarin), large outcomes data of stroke prevention were used to produce a hypothetical control group based on clinical variables in the individual studies (CHADS2 score). Results were stratified according to LAAO device type. Results: We identified 16 studies with a total of 1759 patients receiving LAAO. Summary estimates demonstrate LAAO reduced risk of stroke in comparison with no therapy or aspirin therapy (RR 0.34, 95% CI 0.25-0.46) and in comparison with warfarin therapy (RR 0.65, 95% CI 0.46-0.91, Figure). Summary estimates differed based on the study used to derive the hypothetical control group. Device deployment was unsuccessful in 6.1% of patients and overall complication rate was 7.1%. Efficacy and safety were similar across LAAO device type (Watchman, Plaato, Amplatzer cardiac plug, and Lariat). There was no significant heterogeneity between studies using the Cochrane Q statistic or the I2 index. Conclusions: Our data suggest that LAAO is a reasonable alternative to anticoagulation therapy. Data was limited with the use of most available devices. To better establish the risk and benefit of LAAO in comparison with standard therapy, more randomized controlled trials are necessary.
Mother and Child Health. Delivering the Services.
Authors: Cicely D. Williams, Derrick Brian Jelliffe
Journal: Annals of Internal Medicine (1973)

General introduction 1. Cultural factors 2. Historical developments 3. The reasons for mother and child health services 4. Population problems 5. Women's health problems and status 6. Common problems in children 7. Nutrition and malnutrition 8. Measurement of health 9. Health education 10. Health services for mothers 11. Health services for children 12. Health services for school-aged children 13. Special programs 14. Organization 15. Personnel and training 16. Delivery the services