tbuckley/cabot-search huggingface dataset:
Assessment of pneumonia severity: a European perspective
Authors: S. Ewig, A. Torres, M. Woodhead
Journal: European Respiratory Journal (2005)

here to treat a patient with community-acquired pneumonia (CAP) is probably the most important decision in the management of this condition.This is true in terms of patient outcomes and, definitely, in terms of costs.Therefore, all current European and American guidelines agree that the assessment of severity is the starting point in the management algorithm [1][2][3][4][5].If the assessment is so crucial, what are the criteria physicians can rely on?
T Helper Cell Type 2 Cytokines Coordinately Regulate Immunoglobulin E–Dependent Cysteinyl Leukotriene Production by Human Cord Blood–Derived Mast Cells
Authors: Fred H. Hsieh, Bing K. Lam, John F. Penrose, K. Frank Austen, Joshua A. Boyce
Journal: The Journal of Experimental Medicine (2001)

Human mast cells (hMCs) derived in vitro from cord blood mononuclear cells exhibit stem cell factor (SCF)-dependent comitogenic responses to T helper cell type 2 (Th2) cytokines. As cysteinyl leukotriene (cys-LT) biosynthesis is a characteristic of immunoglobulin (Ig)E-activated mucosal hMCs, we speculated that Th2 cytokines might regulate eicosanoid generation by hMCs. After passive sensitization for 5 d with IgE in the presence of SCF, anti-IgE–stimulated hMCs elaborated minimal cys-LT (0.1 ± 0.1 ng/106 hMCs) and abundant prostaglandin (PG)D2 (16.2 ± 10.3 ng/106 hMCs). Priming of hMCs by interleukin (IL)-4 with SCF during passive sensitization enhanced their anti-IgE–dependent histamine exocytosis and increased their generation of both cys-LT (by 27-fold) and PGD2 (by 2.5-fold). Although priming with IL-3 or IL-5 alone for 5 d with SCF minimally enhanced anti-IgE–mediated cys-LT generation, these cytokines induced further six- and fourfold increases, respectively, in IgE-dependent cys-LT generation when provided with IL-4 and SCF; this occurred without changes in PGD2 generation or histamine exocytosis relative to hMCs primed with IL-4 alone. None of these cytokines, either alone or in combination, substantially altered the levels of cytosolic phospholipase A2 (cPLA2), 5-lipoxygenase (5-LO), or 5-LO activating protein (FLAP) protein expression by hMCs. In contrast, IL-4 priming dramatically induced the steady-state expression of leukotriene C4 synthase (LTC4S) mRNA within 6 h, and increased the expression of LTC4S protein and functional activity in a dose- and time-dependent manner, with plateaus at 10 ng/ml and 5 d, respectively. Priming by either IL-3 or IL-5, with or without IL-4, supported the localization of 5-LO to the nucleus of hMCs. Thus, different Th2-derived cytokines target distinct steps in the 5-LO/LTC4S biosynthetic pathway (induction of LTC4S expression and nuclear import of 5-LO, respectively), each of which is necessary for a full integrated functional response to IgE-dependent activation, thus modulating the effector phenotype of mature hMCs.
Commentary: How good are the epidemiological data?
Authors: N. Noah
Journal: BMJ (1996)

This surveillance system was provoked into existence by the virtual non-functioning of the existing notification system in France. In its 12 years, 330 000 separate episodes of communicable disease from a selected list of eight rubrics have been reported. This gives an average of one diagnosis a week from each of about 500 general practitioners, a surprisingly low rate considering the conditions that are reported. These are an interesting but curious mix, ranging from specific (measles, mumps, chickenpox, and HIV tests) through broad (male urethritis, acute viral hepatitis) to diffuse (acute diarrhoeas, flu-like illness).

The strength of the system is undoubtedly in its technical sophistication. The use of paper is (presumably) minimal or non-existent. Thus the statistics, provided the sentinel …
Cost-Effectiveness of Aliskiren in Type 2 Diabetes, Hypertension, and Albuminuria
Authors: Thomas E. Delea, Oleg Sofrygin, James L. Palmer, Helen Lau, Veronica C. Munk, Jennifer Sung, Alan Charney, Hans-Henrik Parving, Sean D. Sullivan
Journal: Journal of the American Society of Nephrology (2009)

The Aliskiren in the Evaluation of Proteinuria in Diabetes (AVOID) trial demonstrated that adding aliskiren, an oral direct renin inhibitor, at a dosage of 300 mg/d to the highest approved dosage of losartan and optimal antihypertensive therapy reduces albuminuria over 6 mo among patients with type 2 diabetes, hypertension, and albuminuria. The cost-effectiveness of this therapy, however, is unknown. Here, we used a Markov model to project progression to ESRD, life years, quality-adjusted life years, and lifetime costs for aliskiren plus losartan versus losartan. We used data from the AVOID study and the Irbesartan in Diabetic Nephropathy Trial (IDNT) to estimate probabilities of progression of renal disease. We estimated probabilities of mortality for ESRD and other comorbidities using data from the US Renal Data System, US Vital Statistics, and published studies. We based pharmacy costs on wholesale acquisition costs and based costs of ESRD and transplantation on data from the US Renal Data System. We found that adding aliskiren to losartan increased time free of ESRD, life expectancy, and quality-adjusted life expectancy by 0.1772, 0.1021, and 0.0967 yr, respectively. Total expected lifetime health care costs increased by $2952, reflecting the higher pharmacy costs of aliskiren and losartan ($7769), which were partially offset by savings in costs of ESRD ($4860). We estimated the cost-effectiveness of aliskiren to be $30,500 per quality-adjusted life year gained. In conclusion, adding aliskiren to losartan and optimal therapy in patients with type 2 diabetes, hypertension, and albuminuria may be cost-effective from a US health care system perspective.
B cells in autoimmune hepatitis: Friend or foe?
Authors: Jin‐Zhong Dong, Li‐Ping Wang, Jian‐Hua Zhu
Journal: Hepatology (2015)

Potential conflict of interest: Nothing to report. To the Editor: In a recent issue of hepatology, Beland et al.1 reported that depletion of B cells could effectively ameliorate autoimmune hepatitis in mice through reduced antigen presentation and help to T cells. They also demonstrated that administration of a single dose of anti‐CD20 could significantly reduce liver inflammation in mice. However, we are concerned about several experiments in this article. First, the role of B cells in autoimmune hepatitis (AIH) is not clear. The study showed that there are two types of AIH, type 1 (AIH‐1) and type 2 (AIH‐2), characterized by distinct autoimmune serology2; and the pathogenesis of AIH is not fully understood. Hence, in theory, the role of B cells in AIH is controversially discussed. Moreover, Liu et al.3 found that B cells could ameliorate experimental AIH by suppressing CD4+ T‐cell responses. Therefore, whether B cells are friend or foe is still unknown. Is it reasonable to deplete B cells in AIH? Second, the safety of long‐term administration of anti‐CD20 antibody is unknown. Anti‐CD20 antibody may lead to fatal complications. For instance, studies have shown that anti‐CD20 antibody may induce hypotension,4 bronchospasm,5 infectious events,6 and even fulminant hepatitis B reactivation.7 Thus, what is known about the safety of long‐term administration of anti‐CD20 antibody in the treatment of animals or patients with AIH?
Deep sequencing of the X chromosome reveals the proliferation history of colorectal adenomas
Authors: Anna De Grassi, Fabio Iannelli, Matteo Cereda, Sara Volorio, Valentina Melocchi, Alessandra Viel, Gianluca Basso, Luigi Laghi, Michele Caselle, Francesca D Ciccarelli
Journal: Genome biology (2014)

Mismatch repair deficient colorectal adenomas are composed of transformed cells that descend from a common founder and progressively accumulate genomic alterations. The proliferation history of these tumors is still largely unknown. Here we present a novel approach to rebuild the proliferation trees that recapitulate the history of individual colorectal adenomas by mapping the progressive acquisition of somatic point mutations during tumor growth. Using our approach, we called high and low frequency mutations acquired in the X chromosome of four mismatch repair deficient colorectal adenomas deriving from male individuals. We clustered these mutations according to their frequencies and rebuilt the proliferation trees directly from the mutation clusters using a recursive algorithm. The trees of all four lesions were formed of a dominant subclone that co-existed with other genetically heterogeneous subpopulations of cells. However, despite this similar hierarchical organization, the growth dynamics varied among and within tumors, likely depending on a combination of tumor-specific genetic and environmental factors. Our study provides insights into the biological properties of individual mismatch repair deficient colorectal adenomas that may influence their growth and also the response to therapy. Extended to other solid tumors, our novel approach could inform on the mechanisms of cancer progression and on the best treatment choice.
The Effect of Insertions, Deletions, and Alignment Errors on the Branch-Site Test of Positive Selection
Authors: W. Fletcher, Z. Yang
Journal: Molecular Biology and Evolution (2010)

The detection of positive Darwinian selection affecting protein-coding genes remains a topic of great interest and importance. The "branch-site" test is designed to detect localized episodic bouts of positive selection that affect only a few amino acid residues on particular lineages and has been shown to have reasonable power and low false-positive rates for a wide range of selection schemes. Previous simulations examining the performance of the test, however, were conducted under idealized conditions without insertions, deletions, or alignment errors. As the test is sometimes used to analyze divergent sequences, the impact of indels and alignment errors is a major concern. Here, we used a recently developed indel-simulation program to examine the false-positive rate and power of the branch-site test. We find that insertions and deletions do not cause excessive false positives if the alignment is correct, but alignment errors can lead to unacceptably high false positives. Of the alignment methods evaluated, PRANK consistently outperformed MUSCLE, MAFFT, and ClustalW, mostly because the latter programs tend to place nonhomologous codons (or amino acids) into the same column, producing shorter and less accurate alignments and giving the false impression that many amino acid substitutions have occurred at those sites. Our examination of two previous studies suggests that alignment errors may impact the analysis of mammalian and vertebrate genes by the branch-site test, and it is important to use reliable alignment methods.
[37] OUTCOME OF PATIENTS TRANSPLANTED FOR PRIMARY SCLEROSING CHOLANGITIS - ANALYSIS OF THE EUROPEAN LIVER TRANSPLANT REGISTRY
Authors: C. Schramm, M. Bubenheim, J.G. O'Grady, J. Buckels, S. Pollard, P. Neuhaus, N. Jamieson, J. Klempnauer, X. Rogiers, V. Karam, R. Adam, A.W. Lohse
Journal: Journal of Hepatology (2007)
Phase II trial of low-dose continuous (metronomic) treatment of temozolomide for recurrent glioblastoma
Authors: D.-S. Kong, J.-I. Lee, J. H. Kim, S. T. Kim, W. S. Kim, Y.-L. Suh, S. M. Dong, D.-H. Nam
Journal: Neuro-Oncology (2010)

The prognosis for patients with recurrent glioblastomas (GBMs) is dismal, with a median survival of 3-6 months. We performed a phase II trial of low-dose continuous (metronomic) treatment using temozolomide (TMZ) for recurrent GBMs. TMZ-refractory patients with GBM who experienced disease recurrence or progression during or after the cyclic treatment schedule of TMZ after surgery and standard radiotherapy were eligible. This phase II trial included 2 cohorts of patients. The initial cohort, comprising 10 patients, received TMZ at 40 mg/m(2) everyday. After this regimen seemed safe and effective, the metronomic schedule was changed to 50 mg/m(2) everyday. The second cohort, comprising 28 patients, received TMZ at 50 mg/m(2) everyday. The 6-month progression-free survival in all 38 patients was 32.5% (95% CI: 29.3%-35.8%) and the 6-month overall survival was 56.0% (95% CI: 36.2%-75.8%). One patient developed a grade III neutropenia, grade II thrombocytopenia in 3 patients, and grade II increase of liver enzyme (GOT/GPT) in 3 patients. Of all patients included in this study, 4 patients were withdrawn from this study because of side effects including sustained hematological disorders, cryptococcal infection, and cellulitis. In a response group, quality of life measured with short form-36 was well preserved, when compared with the pretreatment status. Metronomic treatment of TMZ is an effective treatment for recurrent GBM that is even refractory to conventional treatment of TMZ and has acceptable toxicity.
Bone Marrow Transplantation Versus Prolonged Intensive Chemotherapy for Children With Acute Lymphoblastic Leukemia and an Initial Bone Marrow Relapse Within 12 Months of the Completion of Primary Therapy: Children's Oncology Group Study CCG-1941
Authors: Paul S. Gaynon, Richard E. Harris, Arnold J. Altman, Bruce C. Bostrom, John C. Breneman, Ria Hawks, David Steele, Theodore Zipf, Daniel O. Stram, Doodjuen Villaluna, Michael E. Trigg
Journal: Journal of Clinical Oncology (2006)

To compare conventional sibling bone marrow transplantation (CBMT), BMT with alternative donor (ABMT), and chemotherapy (CT) for children with acute lymphoblastic leukemia (ALL) and an early first marrow relapse.After informed consent, 214 patients with ALL and early marrow relapse began multiagent induction therapy. One hundred sixty-three patients with fewer than 25% marrow blasts and count recovery at the end of induction (second remission [CR2]) were allocated by donor availability. Fifty patients with sibling donors were allocated to CBMT. Seventy-two patients were randomly allocated between ABMT and CT while 41 patients refused allocation.Overall, 3-year event free survival from entry is 19% +/- 3%. Thirty-two of 50 CBMT patients (64%) and 19 of 37 ABMT patients (51%) underwent transplantation in CR2 with 3-year disease-free survival of 42% +/- 7% and 29% +/- 7%. The 3-year DFS is 29% +/- 7%, 21% +/- 7%, and 27% +/- 8% for patients allocated to CBMT, ABMT, and CT, respectively. Contrary to protocol, 12 of 35 patients allocated to CT underwent BMT in CR2. Of these, five patients died after BMT and 5 patients relapsed.More than one half of patients died, failed reinduction, or relapsed again before 3 months after CR2 (median time to BMT). Intent-to-treat pair-wise comparison of ABMT with CT, CT with CBMT, and CBMT with ABMT yields hazards of 1.2, 1.1, 0.8 with P values of .56, .80, and .36, respectively. Outcomes remain similar and poor for children with ALL and early marrow relapse. BMT is not a complete answer to the challenge of ALL and early marrow relapse.
Concise Guide to Child and Adolescent Psychiatry, Third Editionby Mina K. Dulcan, M.D., D. Richard Martini, M.D., and MaryBeth Lake, M.D. Arlington, Va., American Psychiatric Publishing, 2003, 404 pp, $32.95.
Authors: DAVID M. MARGULIES, MALGORZATA RELJA, GABRIELLE A. CARLSON
Journal: American Journal of Psychiatry (2006)
Structural Effects and Neurofunctional Sequelae of Developmental Exposure to Psychotherapeutic Drugs: Experimental and Clinical Aspects
Authors: Lucio G. Costa, Luca Steardo, Vincenzo Cuomo
Journal: Pharmacological Reviews (2004)

The advent of psychotherapeutic drugs has enabled management of mental illness and other neurological problems such as epilepsy in the general population, without requiring hospitalization. The success of these drugs in controlling symptoms has led to their widespread use in the vulnerable population of pregnant women as well, where the potential embryotoxicity of the drugs has to be weighed against the potential problems of the maternal neurological state. This review focuses on the developmental toxicity and neurotoxicity of five broad categories of widely available psychotherapeutic drugs: the neuroleptics, the antiepileptics, the antidepressants, the anxiolytics and mood stabilizers, and a newly emerging class of nonprescription drugs, the herbal remedies. A brief review of nervous system development during gestation and following parturition in mammals is provided, with a description of the development of neurochemical pathways that may be involved in the action of the psychotherapeutic agents. A thorough discussion of animal research and human clinical studies is used to determine the risk associated with the use of each drug category. The potential risks to the fetus, as demonstrated in well described neurotoxicity studies in animals, are contrasted with the often negative findings in the still limited human studies. The potential risk for the human fetus in the continued use of these chemicals without more adequate research is also addressed. The direction of future research using psychotherapeutic drugs should more closely parallel the methodology developed in the animal laboratories, especially since these models have already been used extremely successfully in specific instances in the investigation of neurotoxic agents.
Thymic emigration revisited
Authors: Tom M. McCaughtry, Matthew S. Wilken, Kristin A. Hogquist
Journal: The Journal of Experimental Medicine (2007)

Conventional αβ T cell precursors undergo positive selection in the thymic cortex. When this is successful, they migrate to the medulla and are exposed to tissue-specific antigens (TSA) for purposes of central tolerance, and they undergo maturation to become functionally responsive T cells. It is commonly understood that thymocytes spend up to 2 wk in the medulla undergoing these final maturation steps before emigrating to peripheral lymphoid tissues. In addition, emigration is thought to occur via a stochastic mechanism whereby some progenitors leave early and others leave late—a so-called “lucky dip” process. However, recent research has revealed that medullary thymocytes are a heterogeneous mix of naive αβ T cell precursors, memory T cells, natural killer T cells, and regulatory T cells. Given this, we revisited the question of how long it takes naive αβ T cell precursors to emigrate. We combined the following three approaches to study this question: BrdU labeling, intrathymic injection of a cellular tag, and RAG2p-GFP reporter mice. We established that, on average, naive αβ T cell precursors emigrate only 4–5 d after becoming single-positive (SP) thymocytes. Furthermore, emigration occurs via a strict “conveyor belt” mechanism, where the oldest thymocytes leave first.
Leucovorin, fluorouracil, and oxaliplatin plus bevacizumab versus S-1 and oxaliplatin plus bevacizumab in patients with metastatic colorectal cancer (SOFT): an open-label, non-inferiority, randomised phase 3 trial
Authors: Yasuhide Yamada, Daisuke Takahari, Hiroshi Matsumoto, Hideo Baba, Masato Nakamura, Kazuhiro Yoshida, Motoki Yoshida, Shigeyoshi Iwamoto, Ken Shimada, Yoshito Komatsu, Yasutsuna Sasaki, Taroh Satoh, Keiichi Takahashi, Hideyuki Mishima, Kei Muro, Masahiko Watanabe, Yuh Sakata, Satoshi Morita, Yasuhiro Shimada, Kenichi Sugihara
Journal: The Lancet Oncology (2013)
Increased circulating monocyte activation in patients with unstable coronary syndromes
Authors: Christian V Zalai, M.Dean Kolodziejczyk, Linda Pilarski, Alexander Christov, Patric N Nation, Marita Lundstrom-Hobman, Wayne Tymchak, Vladimir Dzavik, Dennis P Humen, William J Kostuk, George Jablonsky, Peter W Pflugfelder, James E Brown, Alexandra Lucas
Journal: Journal of the American College of Cardiology (2001)
Anti‐angiogenic drugs: from bench to clinical trials
Authors: Ana R. Quesada, Ramón Muñoz‐Chápuli, Miguel A. Medina
Journal: Medicinal Research Reviews (2006)

Abstract Angiogenesis, the generation of new capillaries through a process of pre‐existing microvessel sprouting, is under stringent control and normally occurs only during embryonic and post‐embryonic development, reproductive cycle, and wound repair. However, in many pathological conditions (solid tumor progression, metastasis, diabetic retinopathy, hemangioma, arthritis, psoriasis and atherosclerosis among others), the disease appears to be associated with persistent upregulated angiogenesis. The development of specific anti‐angiogenic agents arises as an attractive therapeutic approach for the treatment of cancer and other angiogenesis‐dependent diseases. The formation of new blood vessels is a complex multi‐step process. Endothelial cells resting in the parent vessels are activated by an angiogenic signal and stimulated to synthesize and release degradative enzymes allowing endothelial cells to migrate, proliferate and finally differentiate to give rise to capillary tubules. Any of these steps may be a potential target for pharmacological intervention. In spite of the disappointing results obtained initially in clinical trials with anti‐angiogenic drugs, recent reports with positive results in phases II and III trials encourage expectations in their therapeutic potential. This review discusses the current approaches for the discovery of new compounds that inhibit angiogenesis, with emphasis on the clinical developmental status of anti‐angiogenic drugs. © 2006 Wiley Periodicals, Inc. Med Res Rev, 26, No. 4, 483–530, 2006
Congenital Tuberculosis
Authors: J. W. Jordan, H. Spencer
Journal: BMJ (1949)

BILMSH 217 diagnosed as having bronchiectasis, had been down-graded to 3, and his discharge from the R.A.F. had been recommended at another hospital.We found no evidence in support of this diagnosis and did not act on the recommendation.Case 7 was also incorrectly labelled " bronchi- ectasis."This seems to be the important point arising from these cases-namely, that a chronic cough and clubbed fingers are not sufficient for a diagnosis of bronchiectasis, with its consequent gloomy prognosis, although it is apparently not rare for this combination to be so evaluated without exclusive investigation having been made. Cases with Unusual FeaturesOther cases showing clubbing that were seen in the same period seem worthy of note because of unusual features.Case 9: Rheumatic Heart Disease.-Aboy aged 8 was admitted with chorea.Two years previously he had had the same malady.There were perfectly typical physical signs of well-established aortic incompetence and mitral stenosis, but there was no suggestion of congenital heart disease in his history or on physical or radiological examination.His fingers and toes were markedly clubbed.There were no signs of heart failure.His parents had not noticed the unusual shape of his fingers until it was pointed out to them.There was no family h-etory of clubbing.Case 10: Cardiac Failure.-Aman aged 53 was admitted to hospital in a state of congestive heart failure, with bilateral hydrothorax.His history of shortness of breath went back six months.There was no history of cough or of previous chest trouble.He showed early but definite clubbing of the fingers.The cause of the heart failure was doubtful; there was no evidence of valvular disease and the blood pressure was not raised, although the apex thrust was beyond the nipple line.After aspiration of the chest and routine treatment an x-ray film of the lungs was entirely clear except for rather heavy root markings.